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Sample records for quinolone antibacterial drug

  1. Overview of drug interactions with the quinolones.

    PubMed

    Davey, P G

    1988-09-01

    Drug interactions with the quinolones are of two types: pharmacokinetic and pharmacodynamic. Pharmacokinetic interactions include inhibition of absorption of quinolones by aluminium and magnesium containing antacids and inhibition of metabolism of other drugs by quinolones. Norfloxacin and ofloxacin are not extensively metabolized and do not inhibit drug metabolism; ciprofloxacin and enoxacin reduce theophylline clearance in normal subjects by less than 50% and greater than 50% respectively. Ciprofloxacin inhibits the metabolism of caffeine, theophylline and antipyrine. The latter is a marker of broad substrate specificity and, until proved otherwise, it would be prudent to avoid combination of ciprofloxacin with drugs which are metabolized and have a low therapeutic index. In addition to theophylline, these include cyclosporin, phenytoin and warfarin. There is evidence that the elderly and patients with liver disease are particularly susceptible to kinetic interactions with ciprofloxacin. In contrast, there is no evidence to suggest that ofloxacin is likely to impair hepatic drug elimination. Enoxacin does not impair the metabolism of chlorpropamide or glibenclamide, it is therefore unlikely that any of the quinolones will interact with sulphonylurea hypoglycaemic drugs. A pharmacodynamic interaction has been demonstrated in vitro between quinolones and non-steroidal anti-inflammatory drugs (NSAIDS) or theophylline. All of these drugs inhibit binding of radio-labelled gamma-amino-butyric acid to mouse synaptic membranes and combinations of quinolones with NSAIDS or theophylline are synergistic. Convulsions have been reported in patients who received a combination of enoxacin with either fenbufen, a NSAID, or theophylline. Like theophylline, NSAIDS undergo hepatic metabolism, so the clinical interaction may be the result of combined pharmacokinetic and pharmacodynamic interactions. Drug-interactions with quinolones are a clinically important problem. Drugs, such as ofloxacin, which do not impair hepatic metabolism of other drugs, have a clinically significant advantage over other quinolones. The pharmacodynamic interaction between quinolones and other GABA inhibitors is extremely poorly documented; further in-vitro, animal and clinical studies are urgently required. PMID:3053579

  2. [The history of the development and changes of quinolone antibacterial agents].

    PubMed

    Takahashi, Hisashi; Hayakawa, Isao; Akimoto, Takeshi

    2003-01-01

    The quinolones, especially the new quinolones (the 6-fluoroquinolones), are the synthetic antibacterial agents to rival the Beta-lactam and the macrolide antibacterials for impact in clinical usage in the antibacterial therapeutic field. They have a broad antibacterial spectrum of activity against Gram-positive, Gram-negative and mycobacterial pathogens as well as anaerobes. Further, they show good-to-moderate oral absorption and tissue penetration with favorable pharmacokinetics in humans resulting in high clinical efficacy in the treatment of many kinds of infections. They also exhibit excellent safety profiles as well as those of oral Beta-lactam antibiotics. The bacterial effects of quinolones inhibit the function of bacterial DNA gyrase and topoisomerase IV. The history of the development of the quinolones originated from nalidixic acid (NA), developed in 1962. In addition, the breakthrough in the drug design for the scaffold and the basic side chains have allowed improvements to be made to the first new quinolone, norfloxacin (NFLX), patented in 1978. Although currently more than 10,000 compounds have been already synthesized in the world, only two percent of them were developed and tested in clinical studies. Furthermore, out of all these compounds, only twenty have been successfully launched into the market. In this paper, the history of the development and changes of the quinolones are described from the first quinolone, NA, via, the first new quinolone (6-fluorinated quinolone) NFLX, to the latest extended-spectrum quinolone antibacterial agents against multi-drug resistant bacterial infections. NA has only modest activity against Gram-negative bacteria and low oral absorption, therefore a suitable candidate for treatment of systemic infections (UTIs) is required. Since the original discovery of NA, a series of quinolones, which are referred to as the old quinolones, have been developed leading to the first new quinolone, NFLX, with moderate improvements in over all properties starting in 1962 through and continuing throughout the 1970's. Especially, the drug design for pipemidic acid (PPA) indicated one of the important breakthroughs that lead to NFLX. The introduction of a piperazinyl group, which ia a basic moiety at the C7-position of the quinolone nuclei, improved activity against Gram-negative organisms broadening the spectrum to include Pseudomonas aeruginosa. PPA also showed soem activity against Gram-positive bac teria. The basic piperazine ring, which can form the zwitterionic natrure with the carboxylic acid at the C3-position, has subsequently been shown to increase the ability of the drugs to penetrate the bacterial cells resulting in enhanced activity. Further, the zwitterionic forms resulted in significant tissue penetration in the pharmacokinetics. On the other hand, the first compound with a fluorine atom at the C6-position of the related quinolone scaffold was flumequine and the compound indicated that activity against Gram-positive bacteria could be improved in the old quinolones. The addition of a flourine atom at the C6-position is essential for the inhibition of target enzymes. The results show the poten antibacterial activity and the penetration of the quinolone molecule into the bacterial cells and human tissue. The real breakthrough came with the combination of these two features in NFLX, a 6-fluorinated quinolone having a piperazinyl group at the C7-position, NFLX features significant differences from the old quinolones in the activities and pharmacokinetics in humans, resulting in high clinical efficacy in the treatment of many kinds of infections including RTIs.Consequently, those great discoveries are rapidly superseded by even better compounds and NFLX proved to be just the beginning of a highly successful period of research into the modifications of the new quinolone antibacterials. Simce the chemical structure and important features of NFLX had become apparent in 1978, many compounds were patented in the next three years, several of which reached the market. Among the drugs, ofloxacin (OFLX) and ciprofloxacin (CPFX) are recognized as superior in several respects to the oral beta-lactam antibiotics as an antibacterial agent. With a focus on OFLX and CPFX, numerous research groups entered the antibacterial therapeutic field, triggering intense competition in the search to find newer, more effective quinolones. After NFLX was introduced in the market, while resulting by the end of today, eleven kinds of other new quinolones launched in Japan. They are enoxacin (ENX), OFLX, CPFX, lomefloxacin (LFLX), fleroxacin (FRLX), tosufloxacin (TFLX), levofloxacin (LVFX), sparfloxacin (SPFX), gatifloxacin (GFLX), prulifloxacin (PULX) and also pazufloxacin (PZFX). The advantages of these compounds, e.g., LVFX, SPFX and GFLX, are that their spectrum includes Gram-positive bacteria species as well as Gram-negative bacteria and they improve bioavailability results when a daily dose is administered for systemic infections including RTIs. However, unexpected adverse reactions, such as the CNS reaction, the drug-drug interaction, phototoxicity, hepatotoxicity and cardiotoxicity such as the QTc interval prolongation of ECG, have been reported in the clinical evaluations or the post-marketing surveillance of several new quinolones. Moreover, the adverse reactions of arthropathy (the joint toxicity) predicated from studies in juvenile animals have never materialized in clinical use. Therefore, no drugs other than NFLX have yet been approved for pediatric use. Fortunately, the newer quinolones are being developed and tested to reduce these adverse reactions on the basis of recent studies. On the other hand, multi-drug resistant Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative staphycolocci (MRCNS), penicillin-resistant Streptococcus pneumoniae (PRSP) and vancomycin-resistant enterococci (VRE) have been a serious problem in the medical community. Recently, the new quinolone antibacterials are highly successful class of antibacterial therapeutic field, however, the increased isolation of quinolone-resistant bacteria above them has become a normal outcome. These problems of multi-drug resistance have been the driving force for the development of newer quinolones. The next gereration of quinolone antibacterial agents will be potent against multi-drug resistant bacteria, such as MRSA, and provide a lower rate of emergence in resistance. Further, they should have favorable safety profiles to reduce the adverse reactions. The future of quinolones as the ultimate in pharmaceuticals must be handled cautiously if they are to realize their potential in the medical community. PMID:15143768

  3. Mechanisms of drug resistance: quinolone resistance.

    PubMed

    Hooper, David C; Jacoby, George A

    2015-09-01

    Quinolone antimicrobials are synthetic and widely used in clinical medicine. Resistance emerged with clinical use and became common in some bacterial pathogens. Mechanisms of resistance include two categories of mutation and acquisition of resistance-conferring genes. Resistance mutations in one or both of the two drug target enzymes, DNA gyrase and DNA topoisomerase IV, are commonly in a localized domain of the GyrA and ParE subunits of the respective enzymes and reduce drug binding to the enzyme-DNA complex. Other resistance mutations occur in regulatory genes that control the expression of native efflux pumps localized in the bacterial membrane(s). These pumps have broad substrate profiles that include quinolones as well as other antimicrobials, disinfectants, and dyes. Mutations of both types can accumulate with selection pressure and produce highly resistant strains. Resistance genes acquired on plasmids can confer low-level resistance that promotes the selection of mutational high-level resistance. Plasmid-encoded resistance is due to Qnr proteins that protect the target enzymes from quinolone action, one mutant aminoglycoside-modifying enzyme that also modifies certain quinolones, and mobile efflux pumps. Plasmids with these mechanisms often encode additional antimicrobial resistances and can transfer multidrug resistance that includes quinolones. Thus, the bacterial quinolone resistance armamentarium is large. PMID:26190223

  4. Overcoming Target-Mediated Quinolone Resistance in Topoisomerase IV by Introducing Metal Ion-Independent Drug-Enzyme Interactions

    PubMed Central

    Aldred, Katie J.; Schwanz, Heidi A.; Li, Gangqin; McPherson, Sylvia A.; Turnbough, Charles L.; Kerns, Robert J.; Osheroff, Neil

    2013-01-01

    Quinolones, which target gyrase and topoisomerase IV, are the most widely prescribed antibacterials worldwide. Unfortunately, their use is threatened by the increasing prevalence of target-mediated drug resistance. Greater than 90% of mutations that confer quinolone resistance act by disrupting enzyme-drug interactions coordinated by a critical water-metal ion bridge. Quinazolinediones are quinolone-like drugs, but lack the skeletal features necessary to support the bridge interaction. These compounds are of clinical interest, however, because they retain activity against the most common quinolone resistance mutations. We utilized a chemical biology approach to determine how quinazolinediones overcome quinolone resistance in Bacillus anthracis topoisomerase IV. Quinazolinediones that retain activity against quinolone-resistant topoisomerase IV do so primarily by establishing novel interactions through the C7 substituent, rather than the drug skeleton. Because some quinolones are highly active against human topoisomerase IIα, we also determined how clinically relevant quinolones discriminate between the bacterial and human enzymes. Clinically relevant quinolones display poor activity against topoisomerase IIα because the human enzyme cannot support drug interactions mediated by the water-metal ion bridge. However, the inclusion of substituents that allow quinazolinediones to overcome topoisomerase IV-mediated quinolone resistance can cause cross-reactivity against topoisomerase IIα. Therefore, a major challenge in designing drugs that overcome quinolone resistance lies in the ability to identify substituents that mediate strong interactions with the bacterial, but not the human, enzymes. Based on our understanding of quinolone-enzyme interactions, we have identified three compounds that display high activity against quinolone-resistant B. anthracis topoisomerase IV but low activity against human topoisomerase IIα. PMID:24047414

  5. Looking for the new preparations for antibacterial therapy III. New antimicrobial agents from the quinolones group in clinical trials.

    PubMed

    Karpiuk, Izabela; Tyski, Stefan

    2013-01-01

    There is an essential need for searching for the new compounds effective in the treatment of infections caused by multidrug-resistant bacteria. This paper is the third part of a series associated with the exploration of new antibacterial agents and it discusses the compounds belonging to the group of quinolones and substances possessing a hybrid structure composed of the quinolone molecule and other compounds. Eleven new substances at the stage of clinical trials are presented. Three of them belong to the group of non-fluorinated quinolone (nemonoxacin, ozenoxacin and KRP-AM 1977X), while six are the quinolones containing fluorine atom at 6 position of the carbon atom in the quinoline ring (zabofloxacin, finafloxacin, delafloxacin, JNJ-Q2, WCK771 and KPI-10). The remaining two compounds possess a hybrid construction composed of the quinolone structure and other molecules (cadazolid and CBR-2092). There is a chance in the near future, that the presented compounds can extend the range of existing antibacterial drugs and provide an alternative to currently available medicinal products. PMID:24340560

  6. 4-Quinolone drugs affect cell cycle progression and function of human lymphocytes in vitro.

    PubMed Central

    Forsgren, A; Schlossman, S F; Tedder, T F

    1987-01-01

    Most antibacterial agents do not affect human lymphocyte function, but a few are inhibitory. In contrast, a pronounced increase in the incorporation of [3H]thymidine in the presence of 4-quinolones was observed in these studies. The uptake of [3H]thymidine into DNA (trichloroacetic acid precipitable) was significantly increased in phytohemagglutinin-stimulated human lymphocytes when they were exposed to eight new 4-quinolone derivatives, ciprofloxacin, norfloxacin, ofloxacin, A-56619, A-56620, amifloxacin, enoxacin, and pefloxacin, at 1.6 to 6.25 micrograms/ml for 5 days. Four less antibacterially active 4-quinolones (nalidixic acid, cinoxacin, flumequine, and pipemidic acid) stimulated [3H]thymidine incorporation only at higher concentrations or not at all. Kinetic studies showed that incorporation of [3H]thymidine was not affected or slightly inhibited by ciprofloxacin 2 days after phytohemagglutinin stimulation but was increased on days 3 to 6. The total incorporation of [3H]thymidine from day 1 to day 6 after phytohemagglutinin stimulation was increased by 42 to 45% at 5 to 20 micrograms of ciprofloxacin per ml. Increased [3H]thymidine incorporation was also seen when human lymphocytes were stimulated with mitogens other than phytohemagglutinin. Ciprofloxacin added at the start of the culture had a more pronounced effect on [3H]thymidine incorporation than when added later. In spite of the apparent increase in DNA synthesis, lymphocyte growth was inhibited by 20 micrograms of ciprofloxacin per ml, and cell cycle analysis showed that ciprofloxacin inhibited progression through the cell cycle. In addition, immunoglobulin secretion by human lymphocytes stimulated by pokeweed mitogen for Epstein-Barr virus was inhibited by approximately 50% at 5 micrograms of ciprofloxacin per ml. These results suggest that the 4-quinolone drugs may also affect eucaryotic cell function in vitro, but additional studies are needed to establish an in vivo relevance. PMID:3606076

  7. Mechanism of Quinolone Action and Resistance

    PubMed Central

    2015-01-01

    Quinolones are one of the most commonly prescribed classes of antibacterials in the world and are used to treat a variety of bacterial infections in humans. Because of the wide use (and overuse) of these drugs, the number of quinolone-resistant bacterial strains has been growing steadily since the 1990s. As is the case with other antibacterial agents, the rise in quinolone resistance threatens the clinical utility of this important drug class. Quinolones act by converting their targets, gyrase and topoisomerase IV, into toxic enzymes that fragment the bacterial chromosome. This review describes the development of the quinolones as antibacterials, the structure and function of gyrase and topoisomerase IV, and the mechanistic basis for quinolone action against their enzyme targets. It will then discuss the following three mechanisms that decrease the sensitivity of bacterial cells to quinolones. Target-mediated resistance is the most common and clinically significant form of resistance. It is caused by specific mutations in gyrase and topoisomerase IV that weaken interactions between quinolones and these enzymes. Plasmid-mediated resistance results from extrachromosomal elements that encode proteins that disrupt quinolone–enzyme interactions, alter drug metabolism, or increase quinolone efflux. Chromosome-mediated resistance results from the underexpression of porins or the overexpression of cellular efflux pumps, both of which decrease cellular concentrations of quinolones. Finally, this review will discuss recent advancements in our understanding of how quinolones interact with gyrase and topoisomerase IV and how mutations in these enzymes cause resistance. These last findings suggest approaches to designing new drugs that display improved activity against resistant strains. PMID:24576155

  8. Antibacterial Spectrum of a Novel Des-Fluoro(6) Quinolone, BMS-284756

    PubMed Central

    Fung-Tomc, Joan C.; Minassian, Beatrice; Kolek, Benjamin; Huczko, Elizabeth; Aleksunes, Lauren; Stickle, Terry; Washo, Thomas; Gradelski, Elizabeth; Valera, Lourdes; Bonner, Daniel P.

    2000-01-01

    The in vitro spectrum of a novel des-fluoro(6) quinolone, BMS-284756, was compared with those of five fluoroquinolones (trovafloxacin, moxifloxacin, levofloxacin, ofloxacin, and ciprofloxacin). BMS-284756 was among the most active and often was the most active quinolone against staphylococci (including methicillin-resistant strains), streptococci, pneumococci (including ciprofloxacin-nonsusceptible and penicillin-resistant strains), and Enterococcus faecalis. BMS-284756 inhibited ≈60 to ≈70% of the Enterococcus faecium (including vancomycin-resistant) strains and 90 to 100% of the Enterobacteriaceae strains and gastroenteric bacillary pathogens at the anticipated MIC susceptible breakpoint (≤4 μg/ml). Against the nonfermenters, BMS-284756 inhibited 90 to 100% of Pseudomonas fluorescens, Pseudomonas stutzeri, Stenotrophomonas maltophilia, Flavobacterium spp., and Acinetobacter spp. and 72% of Pseudomonas aeruginosa strains at 4 μg/ml. Against anaerobic bacteria, BMS-284756 was among the most active, inhibiting essentially all strains tested. It had very low MICs against the fastidious and atypical microbial species, in particular against mycoplasmas or ureaplasmas, Borrelia burgdorferi, chlamydia, and gonococci. These results indicate that with its broad antibacterial spectrum, BMS-284756 should be evaluated clinically for the treatment of community and nosocomial infections. PMID:11083639

  9. DNA Gyrase Is the Target for the Quinolone Drug Ciprofloxacin in Arabidopsis thaliana*

    PubMed Central

    Evans-Roberts, Katherine M.; Mitchenall, Lesley A.; Wall, Melisa K.; Leroux, Julie; Mylne, Joshua S.; Maxwell, Anthony

    2016-01-01

    The Arabidopsis thaliana genome contains four genes that were originally annotated as potentially encoding DNA gyrase: ATGYRA, ATGYRB1, ATGYRB2, and ATGYRB3. Although we subsequently showed that ATGYRB3 does not encode a gyrase subunit, the other three genes potentially encode subunits of a plant gyrase. We also showed evidence for the existence of supercoiling activity in A. thaliana and that the plant is sensitive to quinolone and aminocoumarin antibiotics, compounds that target DNA gyrase in bacteria. However, it was not possible at that time to show whether the A. thaliana genes encoded an active gyrase enzyme, nor whether that enzyme is indeed the target for the quinolone and aminocoumarin antibiotics. Here we show that an A. thaliana mutant resistant to the quinolone drug ciprofloxacin has a point mutation in ATGYRA. Moreover we show that, as in bacteria, the quinolone-sensitive (wild-type) allele is dominant to the resistant gene. Further we have heterologously expressed ATGYRA and ATGYRB2 in a baculovirus expression system and shown supercoiling activity of the partially purified enzyme. Expression/purification of the quinolone-resistant A. thaliana gyrase yields active enzyme that is resistant to ciprofloxacin. Taken together these experiments now show unequivocally that A. thaliana encodes an organelle-targeted DNA gyrase that is the target of the quinolone drug ciprofloxacin; this has important consequences for plant physiology and the development of herbicides. PMID:26663076

  10. DNA Gyrase Is the Target for the Quinolone Drug Ciprofloxacin in Arabidopsis thaliana.

    PubMed

    Evans-Roberts, Katherine M; Mitchenall, Lesley A; Wall, Melisa K; Leroux, Julie; Mylne, Joshua S; Maxwell, Anthony

    2016-02-12

    The Arabidopsis thaliana genome contains four genes that were originally annotated as potentially encoding DNA gyrase: ATGYRA, ATGYRB1, ATGYRB2, and ATGYRB3. Although we subsequently showed that ATGYRB3 does not encode a gyrase subunit, the other three genes potentially encode subunits of a plant gyrase. We also showed evidence for the existence of supercoiling activity in A. thaliana and that the plant is sensitive to quinolone and aminocoumarin antibiotics, compounds that target DNA gyrase in bacteria. However, it was not possible at that time to show whether the A. thaliana genes encoded an active gyrase enzyme, nor whether that enzyme is indeed the target for the quinolone and aminocoumarin antibiotics. Here we show that an A. thaliana mutant resistant to the quinolone drug ciprofloxacin has a point mutation in ATGYRA. Moreover we show that, as in bacteria, the quinolone-sensitive (wild-type) allele is dominant to the resistant gene. Further we have heterologously expressed ATGYRA and ATGYRB2 in a baculovirus expression system and shown supercoiling activity of the partially purified enzyme. Expression/purification of the quinolone-resistant A. thaliana gyrase yields active enzyme that is resistant to ciprofloxacin. Taken together these experiments now show unequivocally that A. thaliana encodes an organelle-targeted DNA gyrase that is the target of the quinolone drug ciprofloxacin; this has important consequences for plant physiology and the development of herbicides. PMID:26663076

  11. Mycobacterium tuberculosis DNA Gyrase: Interaction with Quinolones and Correlation with Antimycobacterial Drug Activity

    PubMed Central

    Aubry, Alexandra; Pan, Xiao-Su; Fisher, L. Mark; Jarlier, Vincent; Cambau, Emmanuelle

    2004-01-01

    Genome studies suggest that DNA gyrase is the sole type II topoisomerase and likely the unique target of quinolones in Mycobacterium tuberculosis. Despite the emerging importance of quinolones in the treatment of mycobacterial disease, the slow growth and high pathogenicity of M. tuberculosis have precluded direct purification of its gyrase and detailed analysis of quinolone action. To address these issues, we separately overexpressed the M. tuberculosis DNA gyrase GyrA and GyrB subunits as His-tagged proteins in Escherichia coli from pET plasmids carrying gyrA and gyrB genes. The soluble 97-kDa GyrA and 72-kDa GyrB subunits were purified by nickel chelate chromatography and shown to reconstitute an ATP-dependent DNA supercoiling activity. The drug concentration that inhibited DNA supercoiling by 50% (IC50) was measured for 22 different quinolones, and values ranged from 2 to 3 μg/ml (sparfloxacin, sitafloxacin, clinafloxacin, and gatifloxacin) to >1,000 μg/ml (pipemidic acid and nalidixic acid). By comparison, MICs measured against M. tuberculosis ranged from 0.12 μg/ml (for gatifloxacin) to 128 μg/ml (both pipemidic acid and nalidixic acid) and correlated well with the gyrase IC50s (R2 = 0.9). Quinolones promoted gyrase-mediated cleavage of plasmid pBR322 DNA due to stabilization of the cleavage complex, which is thought to be the lethal lesion. Surprisingly, the measured concentrations of drug inducing 50% plasmid linearization correlated less well with the MICs (R2 = 0.7). These findings suggest that the DNA supercoiling inhibition assay may be a useful screening test in identifying quinolones with promising activity against M. tuberculosis. The quinolone structure-activity relationship demonstrated here shows that C-8, the C-7 ring, the C-6 fluorine, and the N-1 cyclopropyl substituents are desirable structural features in targeting M. tuberculosis gyrase. PMID:15047530

  12. [Sensitivity spectrum of Francisella tularensis to antibiotics and synthetic antibacterial drugs].

    PubMed

    Vasi'lev, N T; Oborin, V A; Vasi'lev, P G; Glushkova, O V; Kravets, I D; Levchuk, B A

    1989-09-01

    Sensitivity of 6 F. tularensis strains to 57 antibiotics and synthetic antibacterial drugs was studied. It was shown that the strains were highly sensitive to aminoglycosides, tetracyclines, anzamycins, quinolones, chloramphenicol, nitrofurantoin, nitroxoline, novobiocin and fusidin and resistant to penicillins, cephalosporins, polypeptides, vancomycin and sulfanylamides. The interrace differences in F. tularensis could be detected only by sensitivity to erythromycin, oleandomycin and spiramycin. There was observed no cross resistance to streptomycin and other aminoglycosides in F. tularensis. Assay of F. tularensis sensitivity to antibacterial drugs of various groups with the rapid photometric procedure and the agar diffusion method revealed that the results were highly comparable. PMID:2610533

  13. Recent advances in antibacterial drugs

    PubMed Central

    Rai, Jaswant; Randhawa, Gurpreet Kaur; Kaur, Mandeep

    2013-01-01

    The incidence of antimicrobial resistance is on continued rise with a threat to return to the “pre-antibiotic” era. This has led to emergence of such bacterial infections which are essentially untreatable by the current armamentarium of available treatment options. Various efforts have been made to develop the newer antimicrobials with novel modes of action which can act against these multi-drug resistant strains. This review aims to focus on these newly available and investigational antibacterials approved after year 2000, their mechanism of actions/resistance, and spectrum of activity and their phases of clinical trials. Newer unexploited targets and strategies for the next generation of antimicrobial drugs for combating the drug resistance and emerging pathogens in the 21st century have also been reviewed in the present article. PMID:23776832

  14. Topoisomerase IV-quinolone interactions are mediated through a water-metal ion bridge: mechanistic basis of quinolone resistance

    PubMed Central

    Aldred, Katie J.; McPherson, Sylvia A.; Turnbough, Charles L.; Kerns, Robert J.; Osheroff, Neil

    2013-01-01

    Although quinolones are the most commonly prescribed antibacterials, their use is threatened by an increasing prevalence of resistance. The most common causes of quinolone resistance are mutations of a specific serine or acidic residue in the A subunit of gyrase or topoisomerase IV. These amino acids are proposed to serve as a critical enzyme-quinolone interaction site by anchoring a water-metal ion bridge that coordinates drug binding. To probe the role of the proposed water-metal ion bridge, we characterized wild-type, GrlAE85K, GrlAS81F/E85K, GrlAE85A, GrlAS81F/E85A and GrlAS81F Bacillus anthracis topoisomerase IV, their sensitivity to quinolones and related drugs and their use of metal ions. Mutations increased the Mg2+ concentration required to produce maximal quinolone-induced DNA cleavage and restricted the divalent metal ions that could support quinolone activity. Individual mutation of Ser81 or Glu85 partially disrupted bridge function, whereas simultaneous mutation of both residues abrogated protein–quinolone interactions. Results provide functional evidence for the existence of the water-metal ion bridge, confirm that the serine and glutamic acid residues anchor the bridge, demonstrate that the bridge is the primary conduit for interactions between clinically relevant quinolones and topoisomerase IV and provide a likely mechanism for the most common causes of quinolone resistance. PMID:23460203

  15. Quinolone penetration into canine vaginal and urethral secretions.

    PubMed

    Gasser, T C; Graversen, P H; Larsen, E H; Dørflinger, T

    1987-01-01

    Four newer quinolones (amifloxacin, ciprofloxacin, enoxacin, norfloxacin) were administered to female dogs by intravenous infusion. Drug concentrations in plasma, urine, and vaginal and urethral secretion were determined by bioassay. All four quinolones penetrated into vaginal and urethral secretion in concentrations several times higher than the MIC against common urinary pathogens, ciprofloxacin and norfloxacin reaching concentrations exceeding the simultaneous plasma concentrations. Because of their favorable antibacterial spectra, new quinolones should be investigated clinically for the treatment of recurrent urinary tract infection and bacterial vaginitis. PMID:3481457

  16. Newer Antibacterial Drugs for a New Century

    PubMed Central

    Devasahayam, Gina; Scheld, W. Michael; Hoffman, Paul S.

    2010-01-01

    Antibacterial drug discovery and development has slowed considerably in recent years with novel classes discovered decades ago and regulatory approvals tougher to get. This article describes newer classes of antibacterial drugs introduced or approved after year 2000, their mechanisms of action/ resistance, improved analogs, spectrum of activity and clinical trials. It also discusses new compounds in development with novel mechanisms of action as well as novel unexploited bacterial targets and strategies which may pave the way for combating drug resistance and emerging pathogens in the 21st century. PMID:20053150

  17. Synthesis and Antibacterial Evaluation of a New Series of N-Alkyl-2-alkynyl/(E)-alkenyl-4-(1H)-quinolones

    PubMed Central

    Wube, Abraham; Guzman, Juan-David; Hfner, Antje; Hochfellner, Christina; Blunder, Martina; Bauer, Rudolf; Gibbons, Simon; Bhakta, Sanjib; Bucar, Franz

    2012-01-01

    To gain further insight into the structural requirements of the aliphatic group at position 2 for their antimycobacterial activity, some N-alkyl-4-(1H)-quinolones bearing position 2 alkynyls with various chain length and triple bond positions were prepared and tested for in vitro antibacterial activity against rapidly-growing strains of mycobacteria, the vaccine strain Mycobacterium bovis BCG, and methicillin-resistant Staphylococcus aureus strains, EMRSA-15 and -16. The compounds were also evaluated for inhibition of ATP-dependent MurE ligase of Mycobacterium tuberculosis. The lowest MIC value of 0.5 mg/L (1.2-1.5 ?M) was found against M. fortuitum and M. smegmatis. These compounds displayed no or only weak toxicity to the human lung fibroblast cell line MRC-5 at 100 ?M concentration. The quinolone derivatives exhibited pronounced activity against the epidemic MRSA strains (EMRSA-15 and -16) with MIC values of 2-128 mg/L (5.3-364.7 ?M), and M. bovis BCG with an MIC value of 25 mg/L (66.0-77.4 ?M). In addition, the compounds inhibited the MurE ligase of M. tuberculosis with moderate to weak activity showing IC50 values of 200-774 ?M. The increased selectivity towards mycobacterial bacilli with reference to MRC-5 cells observed for 2-alkynyl quinolones compared to their corresponding 2-alkenyl analogues serves to highlight the mycobacterial specific effect of the triple bond. Exploration of a terminal bromine atom at the side chain of N-alkyl-2-(E)-alkenyl-4-(1H)-quinolones showed improved antimycobacterial activity whereas a cyclopropyl residue at N-1 was suggested to be detrimental to antibacterial activity. PMID:22777190

  18. Carriage of Class 1 and 2 Integrons in Quinolone, Extended-Spectrum-β-Lactamase-Producing and Multi Drug Resistant E.coli and K.pneumoniae: High Burden of Antibiotic Resistance

    PubMed Central

    Shams, Froogh; Hasani, Alka; Ahangarzadeh Rezaee, Mohammad; Nahaie, Mohammad Reza; Hasani, Akbar; Soroush Bar Haghi, Mohammad Hossein; Pormohammad, Ali; Elli Arbatan, Asghar

    2015-01-01

    Purpose: The study aimed at assessing any association between quinolone resistance, MDR and ESBL production and their relation with the presence of integrons in Esherichia coli and Klebsiella pneumoniae. Methods: E.coli and K.pneumoniae isolated from various clinical infections were fully identified and analyzed for being quinolone resistant. These isolates were further tested for ESBL production, multi drug resistance and carriage of integrons. Results: In total, 135 isolates were confirmed as quinolone resistant. K.pneumoniae was observed as potent ESBL producer in comparison to E.coli. Ciprofloxacin resistance in both organisms was related significantly with the presence of integron class 1, co-presence of class 1 and 2 as well as to the presence of ESBL production (p< 0.001). However, nalidixic acid resistance was related significantly (p< 0.01) with only integron class 1 and to the presence of ESBL production. Class 1 and 2 integrons were found in 73.5% of MDR isolates with 13.2% of them possessing both intI1 and intI2 genes. Conclusion: Prevalence of quinolone resistance together with ESBL production and MDR in E.coli and K.pneumoniae has contributed to the emergence of antibacterial resistance burden. The higher integron prevalence in our isolates advocates the potentiality of these isolates as a source for dissemination of resistance determinants. PMID:26504755

  19. Quinolone-3-Diarylethers: A new class of drugs for a new era of malaria eradication

    PubMed Central

    White, Karen L.; Forquer, Isaac P.; Cross, Richard M.; Marfurt, Jutta; Mather, Michael W.; Delves, Michael J.; Shackleford, David M.; Saenz, Fabian E.; Morrisey, Joanne M.; Steuten, Jessica; Mutka, Tina; Li, Yuexin; Wirjanata, Grennady; Ryan, Eileen; Duffy, Sandra; Kelly, Jane Xu; Sebayang, Boni F.; Zeeman, Anne-Marie; Noviyanti, Rintis; Sinden, Robert E.; Kocken, Clemens H. M.; Price, Ric N.; Avery, Vicky M.; Angulo-Barturen, Iñigo; Jiménez-Díaz, María Belén; Ferrer, Santiago; Herreros, Esperanza; Sanz, Laura M.; Gamo, Francisco-Javier; Bathurst, Ian; Burrows, Jeremy N.; Siegl, Peter; Guy, R. Kiplin; Winter, Rolf W.; Vaidya, Akhil B.; Charman, Susan A.; Kyle, Dennis E.; Manetsch, Roman; Riscoe, Michael K.

    2014-01-01

    Ideally antimalarial drugs can be developed which target multiple life cycle stages, thus impacting prevention, treatment and transmission of disease. Here we introduce 4-(1H)-quinolone-3-diarylethers that are selectively potent inhibitors of the parasite’s mitochondrial cytochrome bc1 complex. These compounds are highly active against the primary human malarias (falciparum and vivax), targeting the parasite at both the liver and blood stages as well as the forms that are crucial to disease transmission: gametocytes ⇒ zygotes ⇒ ookinetes ⇒ oocysts. Chosen as the preclinical candidate, ELQ-300 has good oral bioavailability at efficacious dosages in mice, is metabolically stable, and is highly active in rodent malaria models. Given a low predicted dose in patients and a long predicted half-life, ELQ-300 offers the hope of a new molecule for the treatment, prevention and, ultimately, eradication of malaria. PMID:23515079

  20. Quinolones and coumarins eliminate chloroplasts from Euglena gracilis.

    PubMed

    Krajcovic, J; Ebringer, L; Polnyi, J

    1989-11-01

    Quinolones and coumarins were potent eliminators of chloroplasts from Euglena gracilis. There was a remarkable similarity between antichloroplastic and antibacterial activities of DNA gyrase inhibitors. Quinolones produced 100% chloroplast-free cells in concentrations which do not affect cell viability. Optimal conditions were exponential growth, continuous illumination, and neutral or slightly alkaline pH. Coumarins were more toxic than quinolones. Among the quinolones, ofloxacin was the most potent in eliminating chloroplasts. Among the coumarins, coumermycin A1 was the most potent. New quinolones and coumermycin A1 were able to induce the complete inability of originally green cells to form green colonies after 24 h of drug exposure, while clorobiocin and novobiocin required several days of exposure. Darkness, heat shock (42 degrees C, 10 min), or simultaneous treatment with chloramphenicol or rifampin decreased the potency of DNA gyrase inhibitors for producing chloroplast-free cells. Remarkably, in cells in which division was blocked by three different methods (resting medium, hyperthermic conditions [37 degrees C], or addition of cycloheximide), new quinolones and coumermycin A1 nevertheless eliminated chloroplasts. The antichloroplastic activity of DNA gyrase inhibitors is additional data suggesting an evolutionary relationship between chloroplasts and eubacteria. PMID:2558612

  1. Genotypic diversity of multidrug-, quinolone- and extensively drug-resistant Mycobacterium tuberculosis isolates in Thailand.

    PubMed

    Disratthakit, Areeya; Meada, Shinji; Prammananan, Therdsak; Thaipisuttikul, Iyarit; Doi, Norio; Chaiprasert, Angkana

    2015-06-01

    Drug-resistant tuberculosis (TB), which includes multidrug-resistant (MDR-TB), quinolone-resistant (QR-TB) and extensively drug-resistant tuberculosis (XDR-TB), is a serious threat to TB control. We aimed to characterize the genotypic diversity of drug-resistant TB clinical isolates collected in Thailand to establish whether the emergence of drug-resistant TB is attributable to transmitted resistance or acquired resistance. We constructed the first molecular phylogeny of MDR-TB (n=95), QR-TB (n=69) and XDR-TB (n=28) in Thailand based on spoligotyping and proposed 24-locus multilocus variable-number of tandem repeat analysis (MLVA). Clustering analysis was performed using the unweighted pair group method with arithmetic mean. Spoligotyping identified the Beijing strain (SIT1) as the most predominant genotype (n=139; 72.4%). The discriminatory power of 0.9235 Hunter-Gaston Discriminatory Index (HGDI) with the 15-locus variable-number tandem repeats of mycobacterial interspersed repetitive units typing was improved to a 0.9574 HGDI with proposed 24-locus MLVA, thereby resulting in the subdivision of a large cluster of Beijing strains (SIT1) into 17 subclusters. We identified the spread of drug-resistant TB clones caused by three different MLVA types in the Beijing strain (SIT1) and a specific clone of XDR-TB caused by a rare genotype, the Manu-ancestor strain (SIT523). Overall, 49.5% of all isolates were clustered. These findings suggest that a remarkable transmission of drug-resistant TB occurred in Thailand. The remaining 50% of drug-resistant TB isolates were unique genotypes, which may have arisen from the individual acquisition of drug resistance. Our results suggest that transmitted and acquired resistance have played an equal role in the emergence of drug-resistant TB. Further characterization of whole genome sequences of clonal strains could help to elucidate the mycobacterial genetic factors relevant for drug resistance, transmissibility and virulence. PMID:25847698

  2. Antibacterial drug discovery in the resistance era.

    PubMed

    Brown, Eric D; Wright, Gerard D

    2016-01-21

    The looming antibiotic-resistance crisis has penetrated the consciousness of clinicians, researchers, policymakers, politicians and the public at large. The evolution and widespread distribution of antibiotic-resistance elements in bacterial pathogens has made diseases that were once easily treatable deadly again. Unfortunately, accompanying the rise in global resistance is a failure in antibacterial drug discovery. Lessons from the history of antibiotic discovery and fresh understanding of antibiotic action and the cell biology of microorganisms have the potential to deliver twenty-first century medicines that are able to control infection in the resistance era. PMID:26791724

  3. Possible interaction of quinolone antibiotics with peptide transporter 1 in oral absorption of peptide-mimetic drugs.

    PubMed

    Arakawa, Hiroshi; Kamioka, Hiroki; Kanagawa, Masahiko; Hatano, Yasuko; Idota, Yoko; Yano, Kentaro; Morimoto, Kaori; Ogihara, Takuo

    2016-01-01

    The study investigated whether quinolone antibiotics inhibit the PEPT1-mediated uptake of its substrates. Among the quinolones examined, lomefloxacin, moxifloxacin (MFLX) and purlifloxacin significantly inhibited the uptake of PEPT1 substrate phenylalanine-Ψ(CN-S)-alanine (Phe-Ψ-Ala) in HeLa/PEPT1 cells to 31.6 ± 1.3%, 27.6 ± 2.9%, 36.8 ± 2.2% and 32.6 ± 1.4%, respectively. Further examination showed that MFLX was an uncompetitive inhibitor, with an IC50 value of 4.29 ± 1.29 mm. In addition, MFLX significantly decreased the cephalexin and valacyclovir uptake in HeLa/PEPT1 cells. In an in vivo study in rats, the maximum plasma concentration (Cmax ) of orally administered Phe-Ψ-Ala was significantly decreased in the presence of MFLX (171 ± 1 ng/ml) compared with that in its absence (244 ± 9 ng/ml). The area under the concentration-time curve (AUC) of orally administered Phe-Ψ-Ala in the presence of MFLX (338 ± 50 ng/ml · h) tended to decrease compared with that in its absence (399 ± 75 ng/ml · h). The oral bioavailability of Phe-Ψ-Ala in the presence and absence of MFLX was 41.7 ± 6.2% and 49.2 ± 9.2%, respectively. The results indicate that administration of quinolone antibiotics concomitantly with PEPT1 substrate drugs may potentially result in drug-drug interaction. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26590007

  4. The antibacterial paradox: essential drugs, effectiveness, and cost.

    PubMed Central

    Fasehun, F.

    1999-01-01

    The concept proposed by WHO of an essential drugs list that should comprise drugs corresponding to the health needs of the majority of the people has been embraced by countries, which have adapted it to their needs. In this study, the essential antibacterial drug lists of 16 countries chosen from the six WHO regions are reviewed. Most of these countries include 73% of WHO-recommended essential antibacterials on their lists. However, most are lacking reserve antibacterials, and even some main list antibacterials, which are essential when empirical therapy fails in cases of bacterial resistance. Many factors that may be responsible for the lack of selection of these drugs, not least cost considerations, are discussed. PMID:10212510

  5. Targeted drug-carrying bacteriophages as antibacterial nanomedicines.

    PubMed

    Yacoby, Iftach; Bar, Hagit; Benhar, Itai

    2007-06-01

    While the resistance of bacteria to traditional antibiotics is a major public health concern, the use of extremely potent antibacterial agents is limited by their lack of selectivity. As in cancer therapy, antibacterial targeted therapy could provide an opportunity to reintroduce toxic substances to the antibacterial arsenal. A desirable targeted antibacterial agent should combine binding specificity, a large drug payload per binding event, and a programmed drug release mechanism. Recently, we presented a novel application of filamentous bacteriophages as targeted drug carriers that could partially inhibit the growth of Staphylococcus aureus bacteria. This partial success was due to limitations of drug-loading capacity that resulted from the hydrophobicity of the drug. Here we present a novel drug conjugation chemistry which is based on connecting hydrophobic drugs to the phage via aminoglycoside antibiotics that serve as solubility-enhancing branched linkers. This new formulation allowed a significantly larger drug-carrying capacity of the phages, resulting in a drastic improvement in their performance as targeted drug-carrying nanoparticles. As an example for a potential systemic use for potent agents that are limited for topical use, we present antibody-targeted phage nanoparticles that carry a large payload of the hemolytic antibiotic chloramphenicol connected through the aminoglycoside neomycin. We demonstrate complete growth inhibition toward the pathogens Staphylococcus aureus, Streptococcus pyogenes, and Escherichia coli with an improvement in potency by a factor of approximately 20,000 compared to the free drug. PMID:17404004

  6. Residues of antibacterial drugs in honey from the Italian market.

    PubMed

    Baggio, A; Gallina, A; Benetti, C; Mutinelli, F

    2009-01-01

    Antibacterial drugs are used worldwide for the control of American and, less often, European foulbrood. Their administration is mostly uncontrolled and applied without approved protocols and instructions for use as well as precautionary recommendations. Consequently, this practice is responsible for the contamination of beehive products and contributes to the problem of food safety. According to this situation, 4672 analyses were carried out on 5303 honeys collected from 2001 to 2007. These samples were investigated for antibacterial residues of tetracyclines, sulphonamides, streptomycin, chloramphenicol and tylosin. Honeys were classified according to their origin: imported honey and honey from the Italian market. In the last group (only for samples collected from 2001 to 2004), another type of honey was distinguished: that of local honey. A total of 6.3% of all samples were positive for the antibacterial drugs analysed; in particular, 6.8% of imported honeys and 6.1% of honeys on the Italian market. Only 1.7% of local honey had antibacterial residues. These results are indicative of a rather frequent presence of antibacterial drug residues in both Italian and imported honeys. Furthermore, the data showed that among the active substances analysed, sulphonamides are the most used antibacterial substance followed by tetracyclines, streptomycin, tylosin, and chloramphenicol. Finally, a continuous monitoring programme is needed, accompanied by an education programme to beekeepers on proper hive management. PMID:24784967

  7. Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance.

    PubMed

    Wohlkonig, Alexandre; Chan, Pan F; Fosberry, Andrew P; Homes, Paul; Huang, Jianzhong; Kranz, Michael; Leydon, Vaughan R; Miles, Timothy J; Pearson, Neil D; Perera, Rajika L; Shillings, Anthony J; Gwynn, Michael N; Bax, Benjamin D

    2010-09-01

    Quinolone antibacterials have been used to treat bacterial infections for over 40 years. A crystal structure of moxifloxacin in complex with Acinetobacter baumannii topoisomerase IV now shows the wedge-shaped quinolone stacking between base pairs at the DNA cleavage site and binding conserved residues in the DNA cleavage domain through chelation of a noncatalytic magnesium ion. This provides a molecular basis for the quinolone inhibition mechanism, resistance mutations and invariant quinolone antibacterial structural features. PMID:20802486

  8. Cost-effectiveness and Pricing of Antibacterial Drugs

    PubMed Central

    Verhoef, Talitha I; Morris, Stephen

    2015-01-01

    Growing resistance to antibacterial agents has increased the need for the development of new drugs to treat bacterial infections. Given increasing pressure on limited health budgets, it is important to study the cost-effectiveness of these drugs, as well as their safety and efficacy, to find out whether or not they provide value for money and should be reimbursed. In this article, we systematically reviewed 38 cost-effectiveness analyses of new antibacterial agents. Most studies showed the new antibacterial drugs were cost-effective compared to older generation drugs. Drug pricing is a complicated process, involving different stakeholders, and has a large influence on cost-effectiveness. Value-based pricing is a method to determine the price of a drug at which it can be cost-effective. It is currently unclear what the influence of value-based pricing will be on the prices of new antibacterial agents, but an important factor will be the definition of ‘value’, which as well as the impact of the drug on patient health might also include other factors such as wider social impact and the health impact of disease. PMID:25521641

  9. Cost-effectiveness and pricing of antibacterial drugs.

    PubMed

    Verhoef, Talitha I; Morris, Stephen

    2015-01-01

    Growing resistance to antibacterial agents has increased the need for the development of new drugs to treat bacterial infections. Given increasing pressure on limited health budgets, it is important to study the cost-effectiveness of these drugs, as well as their safety and efficacy, to find out whether or not they provide value for money and should be reimbursed. In this article, we systematically reviewed 38 cost-effectiveness analyses of new antibacterial agents. Most studies showed the new antibacterial drugs were cost-effective compared to older generation drugs. Drug pricing is a complicated process, involving different stakeholders, and has a large influence on cost-effectiveness. Value-based pricing is a method to determine the price of a drug at which it can be cost-effective. It is currently unclear what the influence of value-based pricing will be on the prices of new antibacterial agents, but an important factor will be the definition of 'value', which as well as the impact of the drug on patient health might also include other factors such as wider social impact and the health impact of disease. PMID:25521641

  10. Bacillus anthracis GrlAV96A Topoisomerase IV, a Quinolone Resistance Mutation That Does Not Affect the Water-Metal Ion Bridge

    PubMed Central

    Aldred, Katie J.; Breland, Erin J.; McPherson, Sylvia A.; Turnbough, Charles L.; Kerns, Robert J.

    2014-01-01

    The rise in quinolone resistance is threatening the clinical use of this important class of broad-spectrum antibacterials. Quinolones kill bacteria by increasing the level of DNA strand breaks generated by the type II topoisomerases gyrase and topoisomerase IV. Most commonly, resistance is caused by mutations in the serine and acidic amino acid residues that anchor a water-metal ion bridge that facilitates quinolone-enzyme interactions. Although other mutations in gyrase and topoisomerase IV have been reported in quinolone-resistant strains, little is known regarding their contributions to cellular quinolone resistance. To address this issue, we characterized the effects of the V96A mutation in the A subunit of Bacillus anthracis topoisomerase IV on quinolone activity. The results indicate that this mutation causes an ∼3-fold decrease in quinolone potency and reduces the stability of covalent topoisomerase IV-cleaved DNA complexes. However, based on metal ion usage, the V96A mutation does not disrupt the function of the water-metal ion bridge. A similar level of resistance to quinazolinediones (which do not use the bridge) was seen. V96A is the first topoisomerase IV mutation distal to the water-metal ion bridge demonstrated to decrease quinolone activity. It also represents the first A subunit mutation reported to cause resistance to quinazolinediones. This cross-resistance suggests that the V96A change has a global effect on the structure of the drug-binding pocket of topoisomerase IV. PMID:25246407

  11. Preparation, structure and microbial evaluation of metal complexes of the second generation quinolone antibacterial drug lomefloxacin

    NASA Astrophysics Data System (ADS)

    Sadeek, Sadeek A.; El-Shwiniy, Walaa H.

    2010-09-01

    Lomefloxacinate of Y(III), Zr(IV) and U(VI) were isolated as solids with the general formula; [Y(LFX) 2Cl 2]Cl·12H 2O, [ZrO(LFX) 2Cl]Cl·15H 2O and [UO 2(LFX) 3](NO 3) 2·4H 2O. The new synthesized complexes were characterized with physicochemical and diverse spectroscopic techniques (IR, UV-Vis. and 1H NMR spectroscopies) as well as thermal analyses. In these complexes lomefloxacin act as bidentate ligand bound to the metal ions through the pyridone oxygen and one carboxylate oxygen. The kinetic parameters of thermogravimetric (TGA) and its differential (DTG), such as entropy of activation, activation energy, enthalpy of activation and Gibbs free energy evaluated by using Coats- Redfern and Horowitz- Metzger equations for free lomefloxacin and three complexes were carried out. The bond stretching force constant and length of the U dbnd O bond for the [UO 2(LFX) 3](NO 3) 2·4H 2O complex were calculated. The antimicrobial activity of lomefloxacin and its metal complexes was tested against different bacterial species, such as Staphylococcus aureus ( S. aureus), Escherichia coli ( E. coli) and Pseudomonas aeruginosa ( P. aeruginosa) as Gram-positive and Gram-negative bacterial species and also against two species of antifungal, penicillium ( P. rotatum) and trichoderma ( T. sp.). The three complexes are of a good action against three bacterial species but the Y(III) complex exhibit excellent activity against Pseudomonas aeruginosa ( P. aeruginosa), when compared to the free lomefloxacin.

  12. Metal complexes of the fourth generation quinolone antimicrobial drug gatifloxacin: Synthesis, structure and biological evaluation

    NASA Astrophysics Data System (ADS)

    Sadeek, Sadeek A.; El-Shwiniy, Walaa H.

    2010-08-01

    Three metal complexes of the fourth generation quinolone antimicrobial agent gatifloxacin (GFLX) with Y(ΙΙΙ), Zr(ΙV) and U(VΙ) have been prepared and characterized with physicochemical and spectroscopic techniques. In these complexes, gatifloxacin acts as a bidentate deprotonated ligand bound to the metal through the ketone oxygen and a carboxylato oxygen. The complexes are six-coordinated with distorted octahedral geometry. The kinetic parameters for gatifloxacin and the three prepared complexes have been evaluated from TGA curves by using Coats-Redfern (CR) and Horowitz-Metzeger (HM) methods. The calculated bond length and force constant, F(U dbnd O), for the UO 2 bond in uranyl complex are 1.7522 Å and 639.46 N m -1. The antimicrobial activity of the complexes has been tested against microorganisms, three bacterial species, such as Staphylococcus aureus ( S. aureus), Escherichia coli ( E. coli) and Pseudomonas aeruginosa ( P. aeruginosa) and two fungi species, penicillium ( P. rotatum) and trichoderma ( T. sp.), showing that they exhibit higher activity than free ligand.

  13. Characterization of Salmonella Typhimurium DNA gyrase as a target of quinolones.

    PubMed

    Kongsoi, Siriporn; Yokoyama, Kazumasa; Suprasert, Apinun; Utrarachkij, Fuangfa; Nakajima, Chie; Suthienkul, Orasa; Suzuki, Yasuhiko

    2015-08-01

    Quinolones exhibit good antibacterial activity against Salmonella spp. isolates and are often the choice of treatment for life-threatening salmonellosis due to multi-drug resistant strains. To assess the properties of quinolones, we performed an in vitro assay to study the antibacterial activities of quinolones against recombinant DNA gyrase. We expressed the S. Typhimurium DNA gyrase A (GyrA) and B (GyrB) subunits in Escherichia coli. GyrA and GyrB were obtained at high purity (>95%) by nickel-nitrilotriacetic acid agarose resin column chromatography as His-tagged 97-kDa and 89-kDa proteins, respectively. Both subunits were shown to reconstitute an ATP-dependent DNA supercoiling activity. Drug concentrations that suppressed DNA supercoiling by 50% (IC50 s) or generated DNA cleavage by 25% (CC25 s) demonstrated that quinolones highly active against S. Typhimurium DNA gyrase share a fluorine atom at C-6. The relationships between the minimum inhibitory concentrations (MICs), IC50 s and CC25 s were assessed by estimating a linear regression between two components. MICs measured against S. Typhimurium NBRC 13245 correlated better with IC50 s (R = 0.9988) than CC25 s (R = 0.9685). These findings suggest that the DNA supercoiling inhibition assay may be a useful screening test to identify quinolones with promising activity against S. Typhimurium. The quinolone structure-activity relationship demonstrated here shows that C-8, the C-7 ring, the C-6 fluorine, and N-1 cyclopropyl substituents are desirable structural features in targeting S. Typhimurium gyrase. PMID:25381884

  14. The introduction of antibacterial drug pipemidic acid into the POM field: Syntheses, characterization and antitumor activity

    NASA Astrophysics Data System (ADS)

    Sha, Jing-Quan; Li, Xin; Zhou, Ying-Hua; Yan, Peng-Fei; Li, Guang-Ming; Wang, Cheng

    2011-11-01

    Two new compounds based on polyoxometalates (POMs) and the quinolone antibacterial drug pipemidic acid (HPPA), {[Ni(PPA) 2]H 4[SiW 12O 40]}·HPPA·3H 2O ( 1), and {[Zn(PPA) 2] 2H 4[SiW 12O 40]}·3H 2O ( 2), have been synthesized under hydrothermal conditions and structurally characterized by routine technique. Single-crystal X-Ray diffraction analysis shows that compound 1 is constructed by Keggin clusters grafted by binuclear nickel clusters, isolated HPPA and water molecules, while compound 2 consists of Keggin clusters grafted by binuclear zinc clusters and water molecules. Due to the selection of different transition metal (TM) ions, compounds 1 and 2 exhibit different structures and antitumor activities. Compound 1 possesses 0D structure and shows no antitumor activities. However, compound 2 possesses 1D structure and exhibits higher antitumor activities than its parent compound. The results show that introduction of different TM-PPA moieties onto the polyoxoanion surface can affect not only the final structures but also their antitumor activities.

  15. The evolving role of chemical synthesis in antibacterial drug discovery.

    PubMed

    Wright, Peter M; Seiple, Ian B; Myers, Andrew G

    2014-08-18

    The discovery and implementation of antibiotics in the early twentieth century transformed human health and wellbeing. Chemical synthesis enabled the development of the first antibacterial substances, organoarsenicals and sulfa drugs, but these were soon outshone by a host of more powerful and vastly more complex antibiotics from nature: penicillin, streptomycin, tetracycline, and erythromycin, among others. These primary defences are now significantly less effective as an unavoidable consequence of rapid evolution of resistance within pathogenic bacteria, made worse by widespread misuse of antibiotics. For decades medicinal chemists replenished the arsenal of antibiotics by semisynthetic and to a lesser degree fully synthetic routes, but economic factors have led to a subsidence of this effort, which places society on the precipice of a disaster. We believe that the strategic application of modern chemical synthesis to antibacterial drug discovery must play a critical role if a crisis of global proportions is to be averted. PMID:24990531

  16. The Evolving Role of Chemical Synthesis in Antibacterial Drug Discovery

    PubMed Central

    Wright, Peter M.; Seiple, Ian B.; Myers, Andrew G.

    2015-01-01

    The discovery and implementation of antibiotics in the early twentieth century transformed human health and wellbeing. Chemical synthesis enabled the development of the first antibacterial substances, organoarsenicals and sulfa drugs, but these were soon outshone by a host of more powerful and vastly more complex antibiotics from nature: penicillin, streptomycin, tetracycline, and erythromycin, among others. These primary defences are now significantly less effective as an unavoidable consequence of rapid evolution of resistance within pathogenic bacteria, made worse by widespread misuse of antibiotics. For decades medicinal chemists replenished the arsenal of antibiotics by semisynthetic and to a lesser degree fully synthetic routes, but economic factors have led to a subsidence of this effort, which places society on the precipice of a disaster. We believe that the strategic application of modern chemical synthesis to antibacterial drug discovery must play a critical role if a crisis of global proportions is to be averted. PMID:24990531

  17. Bacterial Transcription as a Target for Antibacterial Drug Development.

    PubMed

    Ma, Cong; Yang, Xiao; Lewis, Peter J

    2016-03-01

    Transcription, the first step of gene expression, is carried out by the enzyme RNA polymerase (RNAP) and is regulated through interaction with a series of protein transcription factors. RNAP and its associated transcription factors are highly conserved across the bacterial domain and represent excellent targets for broad-spectrum antibacterial agent discovery. Despite the numerous antibiotics on the market, there are only two series currently approved that target transcription. The determination of the three-dimensional structures of RNAP and transcription complexes at high resolution over the last 15 years has led to renewed interest in targeting this essential process for antibiotic development by utilizing rational structure-based approaches. In this review, we describe the inhibition of the bacterial transcription process with respect to structural studies of RNAP, highlight recent progress toward the discovery of novel transcription inhibitors, and suggest additional potential antibacterial targets for rational drug design. PMID:26764017

  18. Mechanism of plasmid-mediated quinolone resistance

    PubMed Central

    Tran, John H.; Jacoby, George A.

    2002-01-01

    Quinolones are potent antibacterial agents that specifically target bacterial DNA gyrase and topoisomerase IV. Widespread use of these agents has contributed to the rise of bacterial quinolone resistance. Previous studies have shown that quinolone resistance arises by mutations in chromosomal genes. Recently, a multiresistance plasmid was discovered that encodes transferable resistance to quinolones. We have cloned the plasmid-quinolone resistance gene, termed qnr, and found it in an integron-like environment upstream from qacEΔ1 and sulI. The gene product Qnr was a 218-aa protein belonging to the pentapeptide repeat family and shared sequence homology with the immunity protein McbG, which is thought to protect DNA gyrase from the action of microcin B17. Qnr had pentapeptide repeat domains of 11 and 28 tandem copies, separated by a single glycine with a consensus sequence of A/C D/N L/F X X. Because the primary target of quinolones is DNA gyrase in Gram-negative strains, we tested the ability of Qnr to reverse the inhibition of gyrase activity by quinolones. Purified Qnr-His6 protected Escherichia coli DNA gyrase from inhibition by ciprofloxacin. Gyrase protection was proportional to the concentration of Qnr-His6 and inversely proportional to the concentration of ciprofloxacin. The protective activity of Qnr-His6 was lost by boiling the protein and involved neither quinolone inactivation nor independent gyrase activity. Protection of topoisomerase IV, a secondary target of quinolone action in E. coli, was not evident. How Qnr protects DNA gyrase and the prevalence of this resistance mechanism in clinical isolates remains to be determined. PMID:11943863

  19. Conjugation between quinolone-susceptible bacteria can generate mutations in the quinolone resistance-determining region, inducing quinolone resistance.

    PubMed

    Pitondo-Silva, André; Martins, Vinicius Vicente; Silva, Carolina Fávero da; Stehling, Eliana Guedes

    2015-02-01

    Quinolones are an important group of antibacterial agents that can inhibit DNA gyrase and topoisomerase IV activity. DNA gyrase is responsible for maintaining bacteria in a negatively supercoiled state, being composed of subunits A and B. Topoisomerase IV is a homologue of DNA gyrase and consists of two subunits codified by the parC and parE genes. Mutations in gyrA and gyrB of DNA gyrase may confer resistance to quinolones, and the majority of resistant strains show mutations between positions 67 and 106 of gyrA, a region denoted the quinolone resistance-determining region (QRDR). The most frequent substitutions occur at positions 83 and 87, but little is known about the mechanisms promoting appearance of mutations in the QRDR. The present study proposes that some mutations in the QRDR could be generated as a result of the natural mechanism of conjugation between bacteria in their natural habitat. This event was observed following conjugation in vitro of two different isolates of quinolone-susceptible Pseudomonas aeruginosa, which transferred plasmids of different molecular weights to a recipient strain of Escherichia coli (HB101), also quinolone-susceptible, generating two different transconjugants that presented mutations in DNA gyrase and acquisition of resistance to all quinolones tested. PMID:25262036

  20. Accelerating resistance, inadequate antibacterial drug pipelines and international responses.

    PubMed

    Theuretzbacher, Ursula

    2012-04-01

    The pandemic of multidrug-resistant (MDR) pathogens and their continuing spread is beyond dispute. In contrast to the past, today's antibacterial research and development (R&D) pipelines are nearly dry, failing to provide the flow of novel antibiotics required to match the clinical challenges of the multidrug resistance (MDR) crisis. Concerned over the rapidly worsening potential global healthcare crisis caused by MDR bacteria and the lack of robust drug pipelines, several multinational campaigns have issued policy recommendations and have initiated broad discussion with a goal of stimulating the development of novel antibacterial drugs and technologies. These activities have resulted in intensified co-operation between the USA and the EU. The recently announced extensive 'Action plan against the rising threats from antimicrobial resistance' substantially ramps up action within the EU. In recognising the potential crisis caused by MDR and the limited treatment options, the European Commission decided on an unprecedented approach to drive the search for novel antibiotics by integrating the pharmaceutical industry, the research capacities of universities and small companies supported by public funding along with pricing/reimbursement and regulatory bodies. The European Commission has shown leadership and put action plans in place. Only the future will tell whether these initiatives will help curb the impact of the MDR pandemic. PMID:22341298

  1. Newer Antibacterials in Therapy and Clinical Trials

    PubMed Central

    Paknikar, Simi S; Narayana, Sarala

    2012-01-01

    In order to deal with the rising problem of antibiotic resistance, newer antibacterials are being discovered and added to existing pool. Since the year 2000, however, only four new classes of antibacterials have been discovered. These include the oxazolidinones, glycolipopeptides, glycolipodepepsipeptide and pleuromutilins. Newer drugs were added to existing classes of antibiotics, such as streptogramins, quinolones, beta-lactam antibiotics, and macrolide-, tetracycline- and trimethoprim-related drugs. Most of the antibacterials are directed against resistant S. aureus infections, with very few against resistant gram-negative infections. The following article reviews the antibacterials approved by the FDA after the year 2000 as well as some of those in clinical trials. Data was obtained through a literature search via Pubmed and google as well as a detailed search of our library database. PMID:23181224

  2. The relationship between target-class and the physicochemical properties of antibacterial drugs

    PubMed Central

    Mugumbate, Grace; Overington, John P.

    2015-01-01

    The discovery of novel mechanism of action (MOA) antibacterials has been associated with the concept that antibacterial drugs occupy a differentiated region of physicochemical space compared to human-targeted drugs. With, in broad terms, antibacterials having higher molecular weight, lower log P and higher polar surface area (PSA). By analysing the physicochemical properties of about 1700 approved drugs listed in the ChEMBL database, we show, that antibacterials for whose targets are riboproteins (i.e., composed of a complex of RNA and protein) fall outside the conventional human ‘drug-like’ chemical space; whereas antibacterials that modulate bacterial protein targets, generally comply with the ‘rule-of-five’ guidelines for classical oral human drugs. Our analysis suggests a strong target-class association for antibacterials—either protein-targeted or riboprotein-targeted. There is much discussion in the literature on the failure of screening approaches to deliver novel antibacterial lead series, and linkage of this poor success rate for antibacterials with the chemical space properties of screening collections. Our analysis suggests that consideration of target-class may be an underappreciated factor in antibacterial lead discovery, and that in fact bacterial protein-targets may well have similar binding site characteristics to human protein targets, and questions the assumption that larger, more polar compounds are a key part of successful future antibacterial discovery. PMID:25975639

  3. The anti-bacterial poly(caprolactone)-poly(quaternary ammonium salt) as drug delivery carriers.

    PubMed

    Leng, Mengtian; Hu, Shaodong; Lu, Aijing; Cai, Mengtan; Luo, Xianglin

    2016-04-01

    Anti-bacterial materials play significant role in biomedical field. Researches and applications of new anti-bacterial materials are necessary. Novel linear and star-shaped copolymers of poly(caprolactone)-poly(quaternary ammonium salt) (PCL-PJDMA) were synthesized by a combination of ring-opening polymerization and atom transfer radical polymerization. The structures of the copolymers were confirmed by nuclear magnetic resonance ((1)H-NMR) and Fourier transform infrared spectroscopy. The copolymers self-assembled into ball-shaped micelles with low critical micelle concentration (10(-4)∼10(-3) mg/ml). An anti-bacterial drug, triclosan, was chosen as a model drug to investigate the potential application of the copolymers in drug-controlled release. The anti-bacterial experiments against Escherichia coli indicated that all the copolymer micelles had anti-bacterial ability and drug-loaded star-shaped PCL-PJDMA micelles were the best. The slow release of the drug from the drug-loaded micelles prolonged anti-bacterial effect. Therefore, PCL-PJDMA themselves have not only anti-bacterial ability but also the copolymer micelles can be used as carriers for anti-bacterial drugs. PMID:26615398

  4. Quinolones: from antibiotics to autoinducers

    PubMed Central

    Heeb, Stephan; Fletcher, Matthew P; Chhabra, Siri Ram; Diggle, Stephen P; Williams, Paul; Cámara, Miguel

    2011-01-01

    Since quinine was first isolated, animals, plants and microorganisms producing a wide variety of quinolone compounds have been discovered, several of which possess medicinally interesting properties ranging from antiallergenic and anticancer to antimicrobial activities. Over the years, these have served in the development of many synthetic drugs, including the successful fluoroquinolone antibiotics. Pseudomonas aeruginosa and related bacteria produce a number of 2-alkyl-4(1H)-quinolones, some of which exhibit antimicrobial activity. However, quinolones such as the Pseudomonas quinolone signal and 2-heptyl-4-hydroxyquinoline act as quorum-sensing signal molecules, controlling the expression of many virulence genes as a function of cell population density. Here, we review selectively this extensive family of bicyclic compounds, from natural and synthetic antimicrobials to signalling molecules, with a special emphasis on the biology of P. aeruginosa. In particular, we review their nomenclature and biochemistry, their multiple properties as membrane-interacting compounds, inhibitors of the cytochrome bc1 complex and iron chelators, as well as the regulation of their biosynthesis and their integration into the intricate quorum-sensing regulatory networks governing virulence and secondary metabolite gene expression. PMID:20738404

  5. Metal complex of the first-generation quinolone antimicrobial drug nalidixic acid: structure and its biological evaluation.

    PubMed

    Debnath, Anamika; Mogha, Navin Kumar; Masram, Dhanraj T

    2015-03-01

    A novel binuclear squire planar complex of nalidixic acid with Ag(I) metal ion with the formula [Ag(Nal)2] has been synthesized. The synthesized metal complex was characterized using CHN analysis, Fourier-transformed infra-red (FT-IR), thermo gravimetric analysis (TGA), differential scanning calorimetry (DSC), ultra violet-visible (Uv-vis) and single-crystal X-ray diffraction (XRD). The newly synthesized complex shows more advanced antifungal activity compared to the parent quinolone against four fungi, namely Pythium aphanidermatum, Sclerotinia rolfsii, Rhizoctonia solani and Rhizoctonia bataticola. PMID:25547815

  6. Dysglycemia associated with quinolones.

    PubMed

    El Ghandour, Sarah; Azar, Sami T

    2015-06-01

    Antimicrobial therapy is well known to be associated with fluctuations of blood glucose levels. This review aims at exploring the association between glycemic fluctuations and antibiotics mainly focusing on quinolones. Quinolones are associated with hypoglycemia and hyperglycemia. Several mechanism are proposed to explain this causality. PMID:25466161

  7. Antiplasmodial Drugs in the Gas Phase: A CID and DFT Study of Quinolon-4( 1H)-Imine Derivatives

    NASA Astrophysics Data System (ADS)

    Amorim Madeira, Paulo J.; Sitoe, Ana Raquel Fernandes; Gonçalves, Daniel; Rodrigues, Tiago; Guedes, Rita C.; Lopes, Francisca; Moreira, Rui; Bronze, M. Rosário

    2014-09-01

    The gas-phase behavior of 12 quinolon-4( 1H)-imine derivatives with antiplasmodial activity was investigated using electrospray ionization tandem mass spectrometry together with collision induced dissociation and density functional theory (DFT) calculations. The most probable protonation site was predicted by calculating the proton affinity (PA) values for each possible protonation site and it was found to be the imine nitrogen for all compounds under study. Fragmentation pathways of the protonated molecules were proposed and the assignment of product ion structures was performed taking into account theoretical calculations. The nature of the quinoline substituent was found to influence the gas-phase behavior of the compounds under study. The data acquired allowed to bracket the proton affinity of the quinolin-4-imine scaffold, which can be a useful starting point to choose appropriate references for determining PA values of this scaffold.

  8. 21 CFR 201.24 - Labeling for systemic antibacterial drug products.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... development of drug-resistant bacteria and maintain the effectiveness of (insert name of antibacterial drug... treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (b) In the “Indications and Usage” section, the labeling must state: To reduce the development of drug-resistant...

  9. 21 CFR 201.24 - Labeling for systemic antibacterial drug products.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... development of drug-resistant bacteria and maintain the effectiveness of (insert name of antibacterial drug... treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (b) In the “Indications and Usage” section, the labeling must state: To reduce the development of drug-resistant...

  10. 21 CFR 201.24 - Labeling for systemic antibacterial drug products.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... development of drug-resistant bacteria and maintain the effectiveness of (insert name of antibacterial drug... treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (b) In the “Indications and Usage” section, the labeling must state: To reduce the development of drug-resistant...

  11. 21 CFR 201.24 - Labeling for systemic antibacterial drug products.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... development of drug-resistant bacteria and maintain the effectiveness of (insert name of antibacterial drug... treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (b) In the “Indications and Usage” section, the labeling must state: To reduce the development of drug-resistant...

  12. 21 CFR 201.24 - Labeling for systemic antibacterial drug products.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... development of drug-resistant bacteria and maintain the effectiveness of (insert name of antibacterial drug... treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (b) In the “Indications and Usage” section, the labeling must state: To reduce the development of drug-resistant...

  13. In Vivo and In Vitro Toxicodynamic Analyses of New Quinolone-and Nonsteroidal Anti-Inflammatory Drug-Induced Effects on the Central Nervous System

    PubMed Central

    Kita, Hideki; Matsuo, Hirotami; Takanaga, Hitomi; Kawakami, Junichi; Yamamoto, Koujirou; Iga, Tatsuji; Naito, Mikihiko; Tsuruo, Takashi; Asanuma, Atsushi; Yanagisawa, Keiji; Sawada, Yasufumi

    1999-01-01

    We investigated the correlation between an in vivo isobologram based on the concentrations of new quinolones (NQs) in brain tissue and the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) for the occurrence of convulsions in mice and an in vitro isobologram based on the concentrations of both drugs for changes in the γ-aminobutyric acid (GABA)-induced current response in Xenopus oocytes injected with mRNA from mouse brains in the presence of NQs and/or NSAIDs. After the administration of enoxacin (ENX) in the presence or absence of felbinac (FLB), ketoprofen (KTP), or flurbiprofen (FRP), a synergistic effect was observed in the isobologram based on the threshold concentration in brain tissue between mice with convulsions and those without convulsions. The three NSAIDs did not affect the pharmacokinetic behavior of ENX in the brain. However, the ENX-induced inhibition of the GABA response in the GABAA receptor expressed in Xenopus oocytes was enhanced in the presence of the three NSAIDs. The inhibition ratio profiles of the GABA responses for both drugs were analyzed with a newly developed toxicodynamic model. The inhibitory profiles for ENX in the presence of NSAIDs followed the order KTP (1.2 μM) > FRP (0.3 μM) > FLB (0.2 μM). These were 50- to 280-fold smaller than those observed in the absence of NSAIDs. The inhibition ratio (0.01 to 0.02) of the GABAA receptor in the presence of both drugs was well-fitted to the isobologram based on threshold concentrations of both drugs in brain tissue between mice with convulsions and those without convulsions, despite the presence of NSAIDs. In mice with convulsions, the inhibitory profiles of the threshold concentrations of both drugs in brain tissue of mice with convulsions and those without convulsions can be predicted quantitatively by using in vitro GABA response data and toxicodynamic model. PMID:10223919

  14. Quinolones: Action and Resistance Updated

    PubMed Central

    Drlica, Karl; Hiasa, Hiroshi; Kerns, Robert; Malik, Muhammad; Mustaev, Arkady; Zhao, Xilin

    2009-01-01

    The quinolones trap DNA gyrase and DNA topoisomerase IV on DNA as complexes in which the DNA is broken but constrained by protein. Early studies suggested that drug binding occurs largely along helix-4 of the GyrA (gyrase) and ParC (topoisomerase IV) proteins. However, recent X-ray crystallography shows drug intercalating between the -1 and +1 nucleotides of cut DNA, with only one end of the drug extending to helix-4. These two models may reflect distinct structural steps in complex formation. A consequence of drug-enzyme-DNA complex formation is reversible inhibition of DNA replication; cell death arises from subsequent events in which bacterial chromosomes are fragmented through two poorly understood pathways. In one pathway, chromosome fragmentation stimulates excessive accumulation of highly toxic reactive oxygen species that are responsible for cell death. Quinolone resistance arises stepwise through selective amplification of mutants when drug concentrations are above the MIC and below the MPC, as observed with static agar plate assays, dynamic in vitro systems, and experimental infection of rabbits. The gap between MIC and MPC can be narrowed by compound design that should restrict the emergence of resistance. Resistance is likely to become increasingly important, since three types of plasmid-borne resistance have been reported. PMID:19747119

  15. 78 FR 32669 - New Approaches to Antibacterial Drug Development; Request for Comments

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-31

    ... include new drugs for treatment of hospital-acquired bacterial pneumonia, ventilator-associated bacterial... guidance would be helpful. II. Potential New Study Design Approaches The task force explores novel... study design approaches with potential utility for future antibacterial drug development....

  16. The 2012 Garrod lecture: discovery of antibacterial drugs in the 21st century.

    PubMed

    Chopra, Ian

    2013-03-01

    The discovery and development of antibacterial drugs in the twentieth century were major scientific and medical achievements that have had profound benefits for human society. However, in the twenty-first century the widespread global occurrence of bacteria resistant to the antibiotics and synthetic drugs discovered in the previous century threatens to reverse our ability to treat infectious diseases. Although some new drugs are in development they do not adequately cover growing medical needs. Furthermore, these drugs are mostly derivatives of older classes already in use and therefore prone to existing bacterial resistance mechanisms. Thus, new drug classes are urgently needed. Despite investment in antibacterial drug discovery, no new drug class has been discovered in the past 20 years. In this review, based upon my career as a research scientist in the field of antibacterial drug discovery, I consider some of the technical reasons for the recent failure and look to the future developments that may help to reverse the poor current success rate. Diversification of screening libraries to include new natural products will be important as well as ensuring that the promising drug hits arising from structure-based drug design can achieve effective concentrations at their target sites within the bacterial cell. PMID:23134656

  17. 76 FR 39883 - Design of Clinical Trials for Systemic Antibacterial Drugs for the Treatment of Acute Otitis...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-07

    ... HUMAN SERVICES Food and Drug Administration Design of Clinical Trials for Systemic Antibacterial Drugs... of clinical trials of antibacterial agents for the treatment of acute otitis media (middle ear... effect of tympanocentesis (drainage of fluid from the middle chamber of the ear) in clinical trials,...

  18. Synthesis, characterization, antibacterial activity, SOD mimic and interaction with DNA of drug based copper(II) complexes

    NASA Astrophysics Data System (ADS)

    Patel, Mohan N.; Dosi, Promise A.; Bhatt, Bhupesh S.; Thakkar, Vasudev R.

    2011-02-01

    Novel metal complexes of the second-generation quinolone antibacterial agent enrofloxacin with copper(II) and neutral bidentate ligands have been prepared and characterized with elemental analysis reflectance, IR and mass spectroscopy. Complexes have been screened for their in-vitro antibacterial activity against two Gram (+ve)Staphylococcus aureus, Bacillus subtilis, and three Gram (-ve)Serratia marcescens, Escherichia coli and Pseudomonas aeruginosa organisms using the double dilution technique. The binding of this complex with CT-DNA has been investigated by absorption titration, salt effect and viscosity measurements. Binding constant is ranging from 1.3 × 10 4-3.7 × 10 4. The cleavage ability of complexes has been assessed by gel electrophoresis using pUC19 DNA. The catalytic activity of the copper(II) complexes towards the superoxide anion (O 2rad -) dismutation was assayed by their ability to inhibit the reduction of nitroblue tetrazolium (NBT).

  19. [Sensitivity of Corynebacterium diphtheriae isolated in Saint-Petersburg to antibacterial drugs].

    PubMed

    Gladin, D P; Kozlova, N S; Zaĭtseva, T K; Cherednichenko, A S; Khval', S A

    1999-01-01

    One hundred and thirty strains of Corynebacterium diphtheriae isolated in St. Petersburg (42 toxigenic and 88 nontoxigenic) were tested with the method of serial dilutions in solid media for their susceptibility to 20 antibacterial drugs. The MICs of the drugs for the isolates ranged from < or = 0.015 to > or = 32.0 micrograms/ml. 13 per cent of the isolates was resistant at least to one antibacterial drug. The isolates resistant to erythromycin (11.5 per cent), lincomycin (11.5 per cent) and trimethoprim (8.5 per cent) were most frequent. 3 isolates (2.3 per cent) had multiple resistance to 8 drugs: benzylpenicillin, ampicillin, oxacillin, chloramphenicol, erythromycin, lincomycin, trimethoprim, and nitroxolin. No significant differences in the susceptibility of the toxigenic and nontoxigenic strains of C. diphtheriae were detected. Gentamicin, rifampicin, tetracycline, doxycycline and pefloxacin were the most active antibiotics. PMID:10483500

  20. The 10 x '20 Initiative: pursuing a global commitment to develop 10 new antibacterial drugs by 2020.

    PubMed

    2010-04-15

    The time has come for a global commitment to develop new antibacterial drugs. Current data document the impending disaster due to the confluence of decreasing investment in antibacterial drug research and development concomitant with the documented rapid increase in the level of resistance to currently licensed drugs. Despite the good faith efforts of many individuals, professional societies, and governmental agencies, the looming crisis has only worsened over the past decade. PMID:20214473

  1. Antibacterial drugs as corrosion inhibitors for bronze surfaces in acidic solutions

    NASA Astrophysics Data System (ADS)

    Rotaru, Ileana; Varvara, Simona; Gaina, Luiza; Muresan, Liana Maria

    2014-12-01

    The present study is aiming to investigate the effect of four antibiotics (amoxicillin, ciprofloxacin, doxycycline and streptomycin,) belonging to different classes of antibacterial drugs on bronze corrosion in a solution simulating an acid rain (pH 4). Due to their ability to form protective films on the metal surface, the tested antibiotics act as corrosion inhibitors for bronze. The antibiotics were tested at various concentrations in order to determine the optimal concentration range for the best corrosion inhibiting effect. In evaluating the inhibition efficiency, polarization curves, electrochemical impedance spectroscopy, SEM and XPS measurements were used. Moreover, a correlation between the inhibition efficiency of some antibacterial drugs and certain molecular parameters was determined by quantum chemical computations. Parameters like energies EHOMO and ELUMO and HOMO-LUMO energy gap were used for correlation with the corrosion data.

  2. Antitubercular and antibacterial activity of quinonoid natural products against multi-drug resistant clinical isolates.

    PubMed

    Dey, Diganta; Ray, Ratnamala; Hazra, Banasri

    2014-07-01

    Multi-drug resistant Mycobacterium tuberculosis and other bacterial pathogens represent a major threat to human health. In view of the critical need to augment the current drug regime, we have investigated therapeutic potential of five quinonoids, viz. emodin, diospyrin, plumbagin, menadione and thymoquinone, derived from natural products. The antimicrobial activity of quinonoids was evaluated against a broad panel of multi-drug and extensively drug-resistant tuberculosis (M/XDR-TB) strains, rapid growing mycobacteria and other bacterial isolates, some of which were producers of β-lactamase, Extended-spectrum β-lactamase (ESBL), AmpC β-lactamase, metallo-beta-lactamase (MBL) enzymes, as well as their drug-sensitive ATCC counterparts. All the tested quinones exhibited antimycobacterial and broad spectrum antibacterial activity, particularly against M. tuberculosis (lowest MIC 0.25 µg/mL) and Gram-positive bacteria (lowest MIC <4 µg/mL) of clinical origin. The order of antitubercular activity of the tested quinonoids was plumbagin > emodin ~ menadione ~ thymoquinone > diospyrin, whereas their antibacterial efficacy was plumbagin > menadione ~ thymoquinone > diospyrin > emodin. Furthermore, this is the first evaluation performed on these quinonoids against a broad panel of drug-resistant and drug-sensitive clinical isolates, to the best of our knowledge. PMID:24318724

  3. Machine-Learning Techniques Applied to Antibacterial Drug Discovery

    PubMed Central

    Durrant, Jacob D.; Amaro, Rommie E.

    2014-01-01

    The emergence of drug-resistant bacteria threatens to catapult humanity back to the pre-antibiotic era. Even now, multi-drug-resistant bacterial infections annually result in millions of hospital days, billions in healthcare costs, and, most importantly, tens of thousands of lives lost. As many pharmaceutical companies have abandoned antibiotic development in search of more lucrative therapeutics, academic researchers are uniquely positioned to fill the resulting vacuum. Traditional high-throughput screens and lead-optimization efforts are expensive and labor intensive. Computer-aided drug discovery techniques, which are cheaper and faster, can accelerate the identification of novel antibiotics in an academic setting, leading to improved hit rates and faster transitions to pre-clinical and clinical testing. The current review describes two machine-learning techniques, neural networks and decision trees, that have been used to identify experimentally validated antibiotics. We conclude by describing the future directions of this exciting field. PMID:25521642

  4. Exploring simvastatin, an antihyperlipidemic drug, as a potential topical antibacterial agent

    PubMed Central

    Thangamani, Shankar; Mohammad, Haroon; Abushahba, Mostafa F. N.; Hamed, Maha I.; Sobreira, Tiago J. P.; Hedrick, Victoria E.; Paul, Lake N.; Seleem, Mohamed N.

    2015-01-01

    The rapid rise of bacterial resistance to traditional antibiotics combined with the decline in discovery of novel antibacterial agents has created a global public health crisis. Repurposing existing drugs presents an alternative strategy to potentially expedite the discovery of new antimicrobial drugs. The present study demonstrates that simvastatin, an antihyperlipidemic drug exhibited broad-spectrum antibacterial activity against important Gram-positive (including methicillin-resistant Staphylococcus aureus (MRSA)) and Gram-negative pathogens (once the barrier imposed by the outer membrane was permeabilized). Proteomics and macromolecular synthesis analyses revealed that simvastatin inhibits multiple biosynthetic pathways and cellular processes in bacteria, including selective interference of bacterial protein synthesis. This property appears to assist in simvastatin’s ability to suppress production of key MRSA toxins (α-hemolysin and Panton-Valentine leucocidin) that impair healing of infected skin wounds. A murine MRSA skin infection experiment confirmed that simvastatin significantly reduces the bacterial burden and inflammatory cytokines in the infected wounds. Additionally, simvastatin exhibits excellent anti-biofilm activity against established staphylococcal biofilms and demonstrates the ability to be combined with topical antimicrobials currently used to treat MRSA skin infections. Collectively the present study lays the foundation for further investigation of repurposing simvastatin as a topical antibacterial agent to treat skin infections. PMID:26553420

  5. Exploring simvastatin, an antihyperlipidemic drug, as a potential topical antibacterial agent.

    PubMed

    Thangamani, Shankar; Mohammad, Haroon; Abushahba, Mostafa F N; Hamed, Maha I; Sobreira, Tiago J P; Hedrick, Victoria E; Paul, Lake N; Seleem, Mohamed N

    2015-01-01

    The rapid rise of bacterial resistance to traditional antibiotics combined with the decline in discovery of novel antibacterial agents has created a global public health crisis. Repurposing existing drugs presents an alternative strategy to potentially expedite the discovery of new antimicrobial drugs. The present study demonstrates that simvastatin, an antihyperlipidemic drug exhibited broad-spectrum antibacterial activity against important Gram-positive (including methicillin-resistant Staphylococcus aureus (MRSA)) and Gram-negative pathogens (once the barrier imposed by the outer membrane was permeabilized). Proteomics and macromolecular synthesis analyses revealed that simvastatin inhibits multiple biosynthetic pathways and cellular processes in bacteria, including selective interference of bacterial protein synthesis. This property appears to assist in simvastatin's ability to suppress production of key MRSA toxins (α-hemolysin and Panton-Valentine leucocidin) that impair healing of infected skin wounds. A murine MRSA skin infection experiment confirmed that simvastatin significantly reduces the bacterial burden and inflammatory cytokines in the infected wounds. Additionally, simvastatin exhibits excellent anti-biofilm activity against established staphylococcal biofilms and demonstrates the ability to be combined with topical antimicrobials currently used to treat MRSA skin infections. Collectively the present study lays the foundation for further investigation of repurposing simvastatin as a topical antibacterial agent to treat skin infections. PMID:26553420

  6. Functionalized chalcones with basic functionalities have antibacterial activity against drug sensitive Staphylococcus aureus.

    PubMed

    Liu, X L; Xu, Y J; Go, M L

    2008-08-01

    A library of chalcones with basic functionalities were evaluated for antibacterial activity against drug sensitive strains of Staphylococcus aureus and Escherichia coli. The most active compounds were 2-52 and 2-57 (MIC 6.3 microM S. aureus). These compounds had no activity against E. coli (MIC>100 microM). Both compounds were characterized by a ring A that was substituted with 2-hydroxy-4,6-dimethoxy-3-(1-methylpiperidin-4-yl) groups. The phenolic OH and 1-methylpiperidinyl groups were required for activity but the phenolic OH may play a more critical role. While the compounds were comparable to licochalcone A in terms of antibacterial activity, they caused less hemolysis of sheep erythrocytes at high concentrations (100 microM). It was noted that the structural requirements for limiting hemolytic activity were less stringent than those required for antibacterial activity. The present findings suggest that the chalcone framework is an attractive template for optimization to achieve better potency, lower toxicity and a wider spectrum of antibacterial activity. PMID:18031869

  7. Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin.

    PubMed

    Chan, Pan F; Srikannathasan, Velupillai; Huang, Jianzhong; Cui, Haifeng; Fosberry, Andrew P; Gu, Minghua; Hann, Michael M; Hibbs, Martin; Homes, Paul; Ingraham, Karen; Pizzollo, Jason; Shen, Carol; Shillings, Anthony J; Spitzfaden, Claus E; Tanner, Robert; Theobald, Andrew J; Stavenger, Robert A; Bax, Benjamin D; Gwynn, Michael N

    2015-01-01

    New antibacterials are needed to tackle antibiotic-resistant bacteria. Type IIA topoisomerases (topo2As), the targets of fluoroquinolones, regulate DNA topology by creating transient double-strand DNA breaks. Here we report the first co-crystal structures of the antibacterial QPT-1 and the anticancer drug etoposide with Staphylococcus aureus DNA gyrase, showing binding at the same sites in the cleaved DNA as the fluoroquinolone moxifloxacin. Unlike moxifloxacin, QPT-1 and etoposide interact with conserved GyrB TOPRIM residues rationalizing why QPT-1 can overcome fluoroquinolone resistance. Our data show etoposide's antibacterial activity is due to DNA gyrase inhibition and suggests other anticancer agents act similarly. Analysis of multiple DNA gyrase co-crystal structures, including asymmetric cleavage complexes, led to a 'pair of swing-doors' hypothesis in which the movement of one DNA segment regulates cleavage and religation of the second DNA duplex. This mechanism can explain QPT-1's bacterial specificity. Structure-based strategies for developing topo2A antibacterials are suggested. PMID:26640131

  8. Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin

    PubMed Central

    Chan, Pan F.; Srikannathasan, Velupillai; Huang, Jianzhong; Cui, Haifeng; Fosberry, Andrew P.; Gu, Minghua; Hann, Michael M.; Hibbs, Martin; Homes, Paul; Ingraham, Karen; Pizzollo, Jason; Shen, Carol; Shillings, Anthony J.; Spitzfaden, Claus E.; Tanner, Robert; Theobald, Andrew J.; Stavenger, Robert A.; Bax, Benjamin D.; Gwynn, Michael N.

    2015-01-01

    New antibacterials are needed to tackle antibiotic-resistant bacteria. Type IIA topoisomerases (topo2As), the targets of fluoroquinolones, regulate DNA topology by creating transient double-strand DNA breaks. Here we report the first co-crystal structures of the antibacterial QPT-1 and the anticancer drug etoposide with Staphylococcus aureus DNA gyrase, showing binding at the same sites in the cleaved DNA as the fluoroquinolone moxifloxacin. Unlike moxifloxacin, QPT-1 and etoposide interact with conserved GyrB TOPRIM residues rationalizing why QPT-1 can overcome fluoroquinolone resistance. Our data show etoposide's antibacterial activity is due to DNA gyrase inhibition and suggests other anticancer agents act similarly. Analysis of multiple DNA gyrase co-crystal structures, including asymmetric cleavage complexes, led to a ‘pair of swing-doors' hypothesis in which the movement of one DNA segment regulates cleavage and religation of the second DNA duplex. This mechanism can explain QPT-1's bacterial specificity. Structure-based strategies for developing topo2A antibacterials are suggested. PMID:26640131

  9. Three years of antibacterial consumption in Indonesian Community Health Centers: The application of anatomical therapeutic chemical/defined daily doses and drug utilization 90% method to monitor antibacterial use

    PubMed Central

    Pradipta, Ivan S.; Ronasih, Elis; Kartikawati, Arrum D.; Hartanto, Hartanto; Amelia, Rizki; Febrina, Ellin; Abdulah, Rizky

    2015-01-01

    Context: Irrational use of antibacterial drugs in Community Health-Care Centers (CHCs) may lead to increased resistance, morbidity, and mortality. Aims: The aim of this study was to determine patterns of antibacterial use at CHCs in a district of Indonesia and use this as data for an antibiotic policy. Settings and Design: The observational-descriptive study was conducted in a district of Indonesia to obtain antibacterial use from 2008 to 2010. Subjects and Methods: The data obtained from the report on the use of medicines were classified and processed using the anatomical therapeutic chemical (ATC) and defined daily doses (DDD) method, with DDD/1000 patients as a unit measurement. The number of patients was obtained from attending patients in that research period. The most abundant antibacterial drugs use segment was identified by the drug utilization 90% (DU90%) method. Statistical Analysis Used: Descriptive analysis were performed in this study. Results: Fourteen kinds of antibacterial drugs were used in 61 CHCs. The total of antibacterial drug use during the period 2008–2010 was 871.36 DDD/1000 patients/day. Declining antibacterial use was observed between 2008 and 2010. Six kinds of antibacterial drugs were the most commonly used. The data show that the average use per visit was as high as 24.41 DDD. Conclusions: Amoxicillin, sulfamethoxazole and trimethoprim are antibacterials that have to be reconsidered by physicians for use in the Bandung CHC. The high use of antibacterial drugs, as described in the study, can be used as reference to develop an antimicrobial stewardship program and increase awareness of resistance, adverse drug reaction and drug interaction of antibacterial drugs. PMID:25983606

  10. Machine-learning techniques applied to antibacterial drug discovery.

    PubMed

    Durrant, Jacob D; Amaro, Rommie E

    2015-01-01

    The emergence of drug-resistant bacteria threatens to revert humanity back to the preantibiotic era. Even now, multidrug-resistant bacterial infections annually result in millions of hospital days, billions in healthcare costs, and, most importantly, tens of thousands of lives lost. As many pharmaceutical companies have abandoned antibiotic development in search of more lucrative therapeutics, academic researchers are uniquely positioned to fill the pipeline. Traditional high-throughput screens and lead-optimization efforts are expensive and labor intensive. Computer-aided drug-discovery techniques, which are cheaper and faster, can accelerate the identification of novel antibiotics, leading to improved hit rates and faster transitions to preclinical and clinical testing. The current review describes two machine-learning techniques, neural networks and decision trees, that have been used to identify experimentally validated antibiotics. We conclude by describing the future directions of this exciting field. PMID:25521642

  11. Antibacterial activity and mechanism of action of auranofin against multi-drug resistant bacterial pathogens.

    PubMed

    Thangamani, Shankar; Mohammad, Haroon; Abushahba, Mostafa F N; Sobreira, Tiago J P; Hedrick, Victoria E; Paul, Lake N; Seleem, Mohamed N

    2016-01-01

    Traditional methods employed to discover new antibiotics are both a time-consuming and financially-taxing venture. This has led researchers to mine existing libraries of clinical molecules in order to repurpose old drugs for new applications (as antimicrobials). Such an effort led to the discovery of auranofin, a drug initially approved as an anti-rheumatic agent, which also possesses potent antibacterial activity in a clinically achievable range. The present study demonstrates auranofin's antibacterial activity is a complex process that involves inhibition of multiple biosynthetic pathways including cell wall, DNA, and bacterial protein synthesis. We also confirmed that the lack of activity of auranofin observed against Gram-negative bacteria is due to the permeability barrier conferred by the outer membrane. Auranofin's ability to suppress bacterial protein synthesis leads to significant reduction in the production of key methicillin-resistant Staphylococcus aureus (MRSA) toxins. Additionally, auranofin is capable of eradicating intracellular MRSA present inside infected macrophage cells. Furthermore, auranofin is efficacious in a mouse model of MRSA systemic infection and significantly reduces the bacterial load in murine organs including the spleen and liver. Collectively, this study provides valuable evidence that auranofin has significant promise to be repurposed as a novel antibacterial for treatment of invasive bacterial infections. PMID:26936660

  12. Antibacterial activity and mechanism of action of auranofin against multi-drug resistant bacterial pathogens

    PubMed Central

    Thangamani, Shankar; Mohammad, Haroon; Abushahba, Mostafa F. N.; Sobreira, Tiago J. P.; Hedrick, Victoria E.; Paul, Lake N.; Seleem, Mohamed N.

    2016-01-01

    Traditional methods employed to discover new antibiotics are both a time-consuming and financially-taxing venture. This has led researchers to mine existing libraries of clinical molecules in order to repurpose old drugs for new applications (as antimicrobials). Such an effort led to the discovery of auranofin, a drug initially approved as an anti-rheumatic agent, which also possesses potent antibacterial activity in a clinically achievable range. The present study demonstrates auranofin’s antibacterial activity is a complex process that involves inhibition of multiple biosynthetic pathways including cell wall, DNA, and bacterial protein synthesis. We also confirmed that the lack of activity of auranofin observed against Gram-negative bacteria is due to the permeability barrier conferred by the outer membrane. Auranofin’s ability to suppress bacterial protein synthesis leads to significant reduction in the production of key methicillin-resistant Staphylococcus aureus (MRSA) toxins. Additionally, auranofin is capable of eradicating intracellular MRSA present inside infected macrophage cells. Furthermore, auranofin is efficacious in a mouse model of MRSA systemic infection and significantly reduces the bacterial load in murine organs including the spleen and liver. Collectively, this study provides valuable evidence that auranofin has significant promise to be repurposed as a novel antibacterial for treatment of invasive bacterial infections. PMID:26936660

  13. Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection

    PubMed Central

    Ndieyira, Joseph W.; Watari, Moyu; McKendry, Rachel A.

    2013-01-01

    The cantilever sensor, which acts as a transducer of reactions between model bacterial cell wall matrix immobilized on its surface and antibiotic drugs in solution, has shown considerable potential in biochemical sensing applications with unprecedented sensitivity and specificity1-5. The drug-target interactions generate surface stress, causing the cantilever to bend, and the signal can be analyzed optically when it is illuminated by a laser. The change in surface stress measured with nano-scale precision allows disruptions of the biomechanics of model bacterial cell wall targets to be tracked in real time. Despite offering considerable advantages, multiple cantilever sensor arrays have never been applied in quantifying drug-target binding interactions. Here, we report on the use of silicon multiple cantilever arrays coated with alkanethiol self-assembled monolayers mimicking bacterial cell wall matrix to quantitatively study antibiotic binding interactions. To understand the impact of vancomycin on the mechanics of bacterial cell wall structures1,6,7. We developed a new model1 which proposes that cantilever bending can be described by two independent factors; i) namely a chemical factor, which is given by a classical Langmuir adsorption isotherm, from which we calculate the thermodynamic equilibrium dissociation constant (Kd) and ii) a geometrical factor, essentially a measure of how bacterial peptide receptors are distributed on the cantilever surface. The surface distribution of peptide receptors (p) is used to investigate the dependence of geometry and ligand loading. It is shown that a threshold value of p ~10% is critical to sensing applications. Below which there is no detectable bending signal while above this value, the bending signal increases almost linearly, revealing that stress is a product of a local chemical binding factor and a geometrical factor combined by the mechanical connectivity of reacted regions and provides a new paradigm for design of powerful agents to combat superbug infections. PMID:24192763

  14. Investigation of an Immunoassay with Broad Specificity to Quinolone Drugs by Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Data Sets and Advanced Quantitative Structure-Activity Relationship Analysis.

    PubMed

    Chen, Jiahong; Lu, Ning; Shen, Xing; Tang, Qiushi; Zhang, Chijian; Xu, Jun; Sun, Yuanming; Huang, Xin-An; Xu, Zhenlin; Lei, Hongtao

    2016-04-01

    A polyclonal antibody against the quinolone drug pazufloxacin (PAZ) but with surprisingly broad specificity was raised to simultaneously detect 24 quinolones (QNs). The developed competitive indirect enzyme-linked immunosorbent assay (ciELISA) exhibited limits of detection (LODs) for the 24 QNs ranging from 0.45 to 15.16 ng/mL, below the maximum residue levels (MRLs). To better understand the obtained broad specificity, a genetic algorithm with linear assignment of hypermolecular alignment of data sets (GALAHAD) was used to generate the desired pharmacophore model and superimpose the QNs, and then advanced comparative molecular field analysis (CoMFA) and advanced comparative molecular similarity indices analysis (CoMSIA) models were employed to study the three-dimensional quantitative structure-activity relationship (3D QSAR) between QNs and the antibody. It was found that the QNs could interact with the antibody with different binding poses, and cross-reactivity was mainly positively correlated with the bulky substructure containing electronegative atom at the 7-position, while it was negatively associated with the large bulky substructure at the 1-position of QNs. PMID:26982746

  15. Analysis toward innovative herbal antibacterial and antifungal drugs.

    PubMed

    Dhankhar, Sandeep; Dhankhar, Seema; Kumar, Manish; Ruhil, Sonam; Balhara, Meenakshi; Chhillar, Anil K

    2012-12-01

    The antimicrobial activities of four medicinal plants Argemona mexicana, Achyranthes aspera, Catharanthus roseus, and Syzygium cumini were evaluated against Escherichia coli, Vibrio cholerae, Klebsiella pneumoniae, Proteus vulgaris, Bacillus subtilis, Salmonella typhi and three Aspergillus species. Extracts from Achyranthes aspera and Catharanthus roseus showed the highest antimicrobial potential (MIC 0.375-0.750 mg/ml) while extract from Argemona mexicana and Syzygium cumini, showed less activity. In disc diffusion assay, only eight out of twenty extracts showed antimicrobial activity at a concentration of 25.0 μg/ disc. The GCMS investigation reveals the existence of 2-bornanone; 1, 2-benzenedicarboxylic acid, bis (2-methylpropyl) ester; hexadecanoic acid, methyl ester and hexatriacontane in water extract fraction of C. roseus. The present research article provides a review of some medicinal plants incorporating antimicrobial drugs, together with recent advances in emerging therapeutics in clinical development and related patents for exploitation of herbal medicine. PMID:23072646

  16. 75 FR 37818 - Issues in the Design and Conduct of Clinical Trials for Antibacterial Drug Development; Public...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-30

    ... HUMAN SERVICES Food and Drug Administration Issues in the Design and Conduct of Clinical Trials for... regarding scientific issues in the design and conduct of clinical trials for antibacterial drug development... providers, researchers, academia, industry, and regulators on various aspects of design and conduct...

  17. 77 FR 49450 - Issues in the Design of Clinical Trials of Antibacterial Drugs for the Treatment of Non-Cystic...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-16

    ... Drugs for the Treatment of Non-Cystic Fibrosis Bronchiectasis; Public Workshop AGENCY: Food and Drug... treatment of non-cystic fibrosis (non-CF) bronchiectasis. This public workshop is intended to provide... design of clinical trials of antibacterial agents for the treatment of non-CF bronchiectasis....

  18. An analysis of FDA-approved drugs for infectious disease: antibacterial agents.

    PubMed

    Kinch, Michael S; Patridge, Eric; Plummer, Mark; Hoyer, Denton

    2014-09-01

    Drugs targeting infectious diseases have greatly improved public health. A study to evaluate all US Food and Drug Administration (FDA)-approved new molecular entities (NMEs) reveals that the number of new agents targeting infectious disease peaked during the 1990s and declined rapidly thereafter. Molecules targeting bacterial pathogens represent the most common component of anti-infectives followed by antivirals and antifungals. Focusing on antibacterial agents, an increase in new NMEs predominated from the 1960s through to the 1990s, dropping sharply thereafter. Obsolescence and resistance has eliminated one-third of these drugs. Consequently, the arsenal of antibiotics peaked in 2000 and is declining. Likewise, the number of organizations awarded at least one NME for a bacterial indication has declined to a level not seen in more than a half century. PMID:25043770

  19. Improvement of antibacterial activity of some sulfa drugs through linkage to certain phthalazin-1(2H)-one scaffolds.

    PubMed

    Ibrahim, Hany S; Eldehna, Wagdy M; Abdel-Aziz, Hatem A; Elaasser, Mahmoud M; Abdel-Aziz, Marwa M

    2014-10-01

    RAB1 5 is a lead antibacterial agent in which trimethoprim is linked to phthalazine moiety. Similarly, our strategy in this research depends on the interconnection between some sulfa drugs and certain phthalazin-1(2H)-one scaffolds in an attempt to enhance their antibacterial activity. This approach was achieved through the combination of 4-substituted phthalazin-1(2H)-ones 9a, b or 14a, b with sulfanilamide 1a, sulfathiazole 1b or sulfadiazine 1c through amide linkers 6a, b to produce the target compounds 10a-d and 15a-e, respectively. The antibacterial activity of the newly synthesized compounds showed that all tested compounds have antibacterial activity higher than that of their reference sulfa drugs 1a-c. Compound 10c represented the highest antibacterial activity against Gram-positive bacteria Streptococcus pneumonia and Staphylococcus aureus with MIC = 0.39 μmol/mL. Moreover, compound 10d displayed excellent antibacterial activity against Gram-negative bacteria Escherichia coli and Salmonella typhimurium with MIC = 0.39 and 0.78 μmol/mL, respectively. PMID:25113876

  20. Microwave-assisted Heterocyclic Dicarboxylic Acids as Potential Antifungal and Antibacterial Drugs

    PubMed Central

    Dabholkar, V. V.; Parab, S. D.

    2011-01-01

    A series of new dicarboxylic acid derivatives of 1,3,4-thiadiazines, 1,4-benzopiperizines, 1,4-thiazines, 1,3-thiazoles, 1,3-oxazoles and 1,3-imidazoles have been synthesized in 80-87% yield by the environmentally benign microwave induced technique involving the cyclocondensation of 2,3-dibromosuccinic acid with 2-aminothiophenol, o-phenylene diamine, 1,2,4-triazole, amidinothiocarbamide, amidinocarbamide and guanidine hydrochloride. The structures of all newly synthesized compounds have been established on the basis of analytical and spectral data. Evaluation of antibacterial and antifungal activity showed that almost all compounds exhibited better results than reference drugs thus they could be promising candidates for novel drugs. PMID:22303064

  1. Investigation of the composition and antibacterial activity of Ukrain™ drug using liquid chromatography techniques.

    PubMed

    Jesionek, Wioleta; Fornal, Emilia; Majer-Dziedzic, Barbara; Móricz, Ágnes M; Nowicky, Wassil; Choma, Irena M

    2016-01-15

    The greater celandine (Chelidonium majus L.) has been known for the centuries as a medicinal plant. One of the therapeutic agents based on C. majus is anticancer drug Ukrain™ known as a semi-synthetic C. majus alkaloid derivative. Although there are no doubts about antitumor properties of the drug, there is still controversy about its composition. In this study, Ukrain™ was subjected to TLC and LC-MS/MS analyses to compare it with C. majus alkaloid root extract and to determine its composition. Moreover, microbiological activity of both Ukrain™ and the alkaloid extract were tested against Bacillus subtilis strains using TLC-direct bioautography. Sanguinarine, chelidonine, α-homochelidonie and chelerythrine were found to have antibacterial properties. Besides chelidonine, sanguinarine, chelerythrine, protopine, allocryptopine, homochelidonie, berberine and coptisine reported earlier in literature, the presence of stylopine, norchelidonine, dihydrochelidonine and hydroberberine in Ukrain™ was detected, and here they have been reported for the first time. PMID:26718183

  2. [New antibacterial agents on the market and in the pipeline].

    PubMed

    Kern, W V

    2015-11-01

    After some years of stagnation there have been several new successful developments in the field of antibacterial agents. Most of these new developments have been in conventional antibacterial classes. New drugs among the beta-lactam agents are methicillin-resistant Staphylococcus aureus (MRSA) active cephalosporins (ceftaroline and ceftobiprole) and new combinations of beta-lactam with beta-lactamase inhibitors (ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/relebactam and meropenem/RPX7009). New developments can also be observed among oxazolidinones (tedizolid, radezolid, cadazolid and MRX-I), macrolides/ketolides (modithromycin and solithromycin), aminoglycosides (plazomicin), quinolones (nemonoxacin, delafloxacin and avarofloxacin), tetracyclines (omadacycline and eravacycline) as well as among glycopeptides and lipopeptides (oritavancin, telavancin, dalbavancin and surotomycin). New agents in a very early developmental phase are FabI inhibitors, endolysines, peptidomimetics, lipid A inhibitors, methionyl-tRNA synthetase inhibitors and teixobactin. PMID:26475603

  3. Potential antibacterial activity of triazine dendrimer: Synthesis and controllable drug release properties.

    PubMed

    Vembu, Sandhirakasu; Pazhamalai, Srinivasan; Gopalakrishnan, Mannathusamy

    2015-08-01

    A novel sustained release delivery system of ciprofloxacin was developed. The system consists of a viscosity enhancer plus a penetration enhancer to overcome penetration barriers and loss due to wash-out and thus achieve the desired ciprofloxacin ocular absorption. A macromolecule of piperazine core 1,3,5-triazine dendrimer with eight molecules of ciprofloxacin drug as a surface moiety has been synthesized in five steps. Antibacterial activities of this compound have been investigated for Gram-positive and Gram-negative bacteria like Staphylococcus aureus (mtcc 737), Bacillus subtilis (mtcc 2063), Escherichia coli (mtcc-443), Pseudomonas aeruginosa (mtcc 741) and Proteus mirabilis (mtcc425). It was observed that the influence of hydrophobic and hydrophilic balance per repeat unit of these dendrimer has profound effects for antibacterial activities. The MIC value of the compound very lower at 100 μg/mL(-1) when compared with standard ciprofloxacin at 500 μg/mL(-1). The compound (10) exhibits five times higher activity against tested organisms when compared with ciprofloxacin as standard. The structures of the dendrimers were determined by means of MALDI-TOF MS, NMR and IR studies. The in vitro release of ciprofloxacin from obtained dendrimer was investigated. PMID:26113186

  4. Antibacterial activity of natural spices on multiple drug resistant Escherichia coli isolated from drinking water, Bangladesh

    PubMed Central

    2011-01-01

    Background Spices traditionally have been used as coloring agents, flavoring agents, preservatives, food additives and medicine in Bangladesh. The present work aimed to find out the antimicrobial activity of natural spices on multi-drug resistant Escherichia coli isolates. Methods Anti-bacterial potentials of six crude plant extracts (Allium sativum, Zingiber officinale, Allium cepa, Coriandrum sativum, Piper nigrum and Citrus aurantifolia) were tested against five Escherichia coli isolated from potable water sources at kushtia, Bangladesh. Results All the bacterial isolates were susceptible to undiluted lime-juice. None of them were found to be susceptible against the aqueous extracts of garlic, onion, coriander, pepper and ginger alone. However, all the isolates were susceptible when subjected to 1:1:1 aqueous extract of lime, garlic and ginger. The highest inhibition zone was observed with lime (11 mm). Conclusion Natural spices might have anti-bacterial activity against enteric pathogens and could be used for prevention of diarrheal diseases. Further evaluation is necessary. PMID:21406097

  5. Antibacterial effect of Allium sativum cloves and Zingiber officinale rhizomes against multiple-drug resistant clinical pathogens

    PubMed Central

    Karuppiah, Ponmurugan; Rajaram, Shyamkumar

    2012-01-01

    Objective To evaluate the antibacterial properties of Allium sativum (garlic) cloves and Zingiber officinale (ginger) rhizomes against multi-drug resistant clinical pathogens causing nosocomial infection. Methods The cloves of garlic and rhizomes of ginger were extracted with 95% (v/v) ethanol. The ethanolic extracts were subjected to antibacterial sensitivity test against clinical pathogens. Results Anti-bacterial potentials of the extracts of two crude garlic cloves and ginger rhizomes were tested against five gram negative and two gram positive multi-drug resistant bacteria isolates. All the bacterial isolates were susceptible to crude extracts of both plants extracts. Except Enterobacter sp. and Klebsiella sp., all other isolates were susceptible when subjected to ethanolic extracts of garlic and ginger. The highest inhibition zone was observed with garlic (19.45 mm) against Pseudomonas aeruginosa (P. aeruginosa). The minimal inhibitory concentration was as low as 67.00 µg/mL against P. aeruginosa. Conclusions Natural spices of garlic and ginger possess effective anti-bacterial activity against multi-drug clinical pathogens and can be used for prevention of drug resistant microbial diseases and further evaluation is necessary. PMID:23569978

  6. Nanotechnology approaches for antibacterial drug delivery: Preparation and microbiological evaluation of fusogenic liposomes carrying fusidic acid.

    PubMed

    Nicolosi, Daria; Cupri, Sarha; Genovese, Carlo; Tempera, Gianna; Mattina, Roberto; Pignatello, Rosario

    2015-06-01

    Many antibacterial drugs have some difficulty passing through the bacterial cell membrane, especially if they have a high molecular weight or large spatial structure. Consequently, intrinsic resistance is shown by some bacterial strains. Reduced cell membrane permeability is one of the mechanisms of resistance known for fusidic acid (FUS), a bacteriostatic steroidal compound with activity limited to Gram-positive bacteria. Moreover, the lipophilic character of FUS has been shown to cause drug retention inside the bilayers of cell membranes, preventing its diffusion towards target sites inside the cytoplasm. Targeting antimicrobial agents by means of liposomes may be a valid strategy in the treatment of infections refractory to conventional routes of antimicrobial treatment. On this basis, loading of FUS in fusogenic liposomes (FLs) was planned in this study. Fusogenic small unilamellar vesicles loaded with FUS were produced to evaluate their influence on improving the cell penetration and antibacterial activity of the antibiotic. The produced carriers were technologically characterised and were subjected to an in vitro microbiological assay against several strains of Gram-negative and Gram-positive bacteria. The experimental results showed that encapsulating FUS in a liposomal carrier can improve antimicrobial efficacy and reduce the effective concentration required, probably through putative mechanisms of increased diffusion through the bacterial cell membrane. In fact, whilst free FUS was active only on the tested Gram-positive strains, incubation of FUS-loaded FLs exhibited growth inhibitory activity both against Gram-positive and Gram-negative strains. The lowest MICs were obtained against Staphylococcus epidermidis (≤0.15 μg/mL) and Acinetobacter baumannii (37.5 μg/mL) clinical strains. PMID:25816979

  7. Human-use antibacterial residues in the natural environment of China: implication for ecopharmacovigilance.

    PubMed

    Wang, Jun; He, Bingshu; Hu, Xiamin

    2015-06-01

    Antibacterial residues in the natural environment have been of increasing concern due to their impact on bacteria resistance development and toxicity to natural communities and ultimately to public health. China is a large country with high production and consumption of antibacterials for its population growth and economic development in recent years. In this article, we summarized the current situation of human-use antibacterial pollution in Chinese water (wastewaters, natural and drinking waters) and solid matrices (sludge, sediment, and soil) reported in 33 peer-reviewed papers. We found that, although there are adequate wastewater treatment systems in China, human-use antibacterial residues in the natural environment were reported almost throughout the whole country. Three most frequently prescribed classes of antibacterials in China, including quinolones, macrolides, and β-lactam, were also the predominant classes of residues in Chinese environment, manifested as the high concentration and detection frequency. In view of this alarming situation, we have presented that ecopharmacovigilance (EPV) might be implemented in the antibacterial drug administration of China, as the active participation of the pharmaceutical industry and drug regulatory authorities from the diffuse source of antibacterial pollution. Considering EPV experience of developed countries together with the actual conditions of China, we have identified some approaches that can be taken, including:• Focus on education;• Further strengthening and persevering the antibacterial stewardship strategies and pharmaceutical take-back programs in China;• Designing greener antibacterials with better degradability in the environment;• Implementing environmental risk assessment prior to launch of new drugs;• Strengthening collaboration in EPV-related areas. PMID:25947893

  8. [Norfloxacin: a broad-spectrum quinolone for superficial eye infections].

    PubMed

    Grosset, J

    1990-09-01

    Norfloxacin is a synthetic antibiotic belonging to the fluoroquinolone class. At present, an oral formulation is available and indicated for the treatment of urinary tract infections. Because of the properties of norfloxacin, a 0.3% norfloxacin ophtalmic solution may be used by ophtalmologists. The molecular target of norfloxacin is DNA gyrase that regulates DNA replication. Norfloxacin is a broad spectrum antibiotic. A flurin atome in position 6 is responsible for the broad spectrum of activity as compared with the first generation quinolones. MICs of norfloxacin against Haemophilus influenzae, Neisseria gonorrhoeae, Staphylococcus aureus, Pseudomonas aeruginosa, and enterbacteriaceae are low or intermediate. Norfloxacin is a bactericidal drug of which MBCs are equivalent to or twice as high as MICs against the majority of organisms. The proportion of norfloxacin resistant strains is limited and, at present, no plasmid resistance has been observed. This explains the activity of norfloxacin against clinical isolates whose drug resistance is plasmid-mediated. Norfloxacin resistance is chromosomic, but the mutation rate is low. There is no cross-resistance between quinolones and other classes of drug, with the exception of drug resistance related to changes in the bacterial outer membrane proteins. A low decrease in norfloxacin susceptibility is observed in case of resistance to first generation quinolones. The above-mentioned properties make norfloxacin in ophtalmic solution a first line drug for treatment of superficial ocular infections and a second line drug for treatment of infections due to organisms resistant to other drugs. PMID:2235090

  9. Comparative in vitro activities of nemonoxacin (TG-873870), a novel nonfluorinated quinolone, and other quinolones against clinical isolates.

    PubMed

    Lauderdale, Tsai-Ling; Shiau, Yih-Ru; Lai, Jui-Fen; Chen, Hua-Chien; King, Chi-Hsin R

    2010-03-01

    The in vitro antibacterial activities of nemonoxacin (TG-873870), a novel nonfluorinated quinolone, against 770 clinical isolates were investigated. Nemonoxacin (tested as its malate salt, TG-875649) showed better in vitro activity than ciprofloxacin and levofloxacin against different species of staphylococci, streptococci, and enterococci, Neisseria gonorrhoeae, and Haemophilus influenzae. The in vitro activity of TG-875649 was also comparable to or better than that of moxifloxacin against these pathogens, which included ciprofloxacin-resistant, methicillin-resistant Staphylococcus aureus and levofloxacin-resistant Streptococcus pneumoniae. PMID:20065058

  10. Comparative In Vitro Activities of Nemonoxacin (TG-873870), a Novel Nonfluorinated Quinolone, and Other Quinolones against Clinical Isolates ?

    PubMed Central

    Lauderdale, Tsai-Ling; Shiau, Yih-Ru; Lai, Jui-Fen; Chen, Hua-Chien; King, Chi-Hsin R.

    2010-01-01

    The in vitro antibacterial activities of nemonoxacin (TG-873870), a novel nonfluorinated quinolone, against 770 clinical isolates were investigated. Nemonoxacin (tested as its malate salt, TG-875649) showed better in vitro activity than ciprofloxacin and levofloxacin against different species of staphylococci, streptococci, and enterococci, Neisseria gonorrhoeae, and Haemophilus influenzae. The in vitro activity of TG-875649 was also comparable to or better than that of moxifloxacin against these pathogens, which included ciprofloxacin-resistant, methicillin-resistant Staphylococcus aureus and levofloxacin-resistant Streptococcus pneumoniae. PMID:20065058

  11. Multi-target spectral moments for QSAR and Complex Networks study of antibacterial drugs.

    PubMed

    Prado-Prado, Francisco J; Uriarte, Eugenio; Borges, Fernanda; González-Díaz, Humberto

    2009-11-01

    There are many of pathogen bacteria species which very different susceptibility profile to different antibacterial drugs. There are many drugs described with very different affinity to a large number of receptors. In this work, we selected Drug-Bacteria Pairs (DBPs) of affinity/non-affinity drugs with similar/dissimilar bacteria and represented it as a large network, which may be used to identify drugs that can act on bacteria. Computational chemistry prediction of the biological activity based on one-target Quantitative Structure-Activity Relationship (ot-QSAR) studies substantially increases the potentialities of this kind of networks avoiding time and resource consuming experiments. Unfortunately almost all ot-QSAR models predict the biological activity of drugs against only one bacterial species. Consequently, multi-tasking learning to predict drug's activity against different species with a single model (mt-QSAR) is a goal of major importance. These mt-QSARs offer a good opportunity to construct drug-drug similarity Complex Networks. Unfortunately, almost QSAR models are unspecific or predict activity against only one receptor. To solve this problem, we developed here a multi-bacteria QSAR classification model. The model correctly classifies 202 out of 241 active compounds (83.8%) and 169 out of 200 non-active cases (84.5%). Overall training predictability was 84.13% (371 out of 441 cases). The validation of the model was carried out by means of external predicting series, classifying the model 197 out of 221 (89.4%) cases. In order to show how the model functions in practice a virtual screening was carried out recognizing the model as active 86.7%, 520 out of 600 cases not used in training or predicting series. Outputs of this QSAR model were used as inputs to construct a network. The observed network has 1242 nodes (DBPs), 772,736 edges or DBPs with similar activity (sDBPs). The network predicted has 1031 nodes, 641,377 sDBPs. After edge-to-edge comparison, we have demonstrated that the predicted network is significantly similar to the observed one and both have distribution closer to exponential than to normal. PMID:19631422

  12. Quinolone Resistance: Much More than Predicted

    PubMed Central

    Hernández, Alvaro; Sánchez, María B.; Martínez, José L.

    2011-01-01

    Since quinolones are synthetic antibiotics, it was predicted that mutations in target genes would be the only mechanism through which resistance could be acquired, because there will not be quinolone-resistance genes in nature. Contrary to this prediction, a variety of elements ranging from efflux pumps, target-protecting proteins, and even quinolone-modifying enzymes have been shown to contribute to quinolone resistance. The finding of some of these elements in plasmids indicates that quinolone resistance can be transferable. As a result, there has been a developing interest on the reservoirs for quinolone-resistance genes and on the potential risks associated with the use of these antibiotics in non-clinical environments. As a matter of fact, plasmid-encoded, quinolone-resistance qnr genes originated in the chromosome of aquatic bacteria. Thus the use of quinolones in fish-farming might constitute a risk for the emergence of resistance. Failure to predict the development of quinolone resistance reinforces the need of taking into consideration the wide plasticity of biological systems for future predictions. This plasticity allows pathogens to deal with toxic compounds, including those with a synthetic origin as quinolones. PMID:21687414

  13. In vitro activity of subinhibitory concentrations of quinolones on urea-splitting bacteria: effect on urease activity and on cell surface hydrophobicity.

    PubMed

    Ramadan, M A; Tawfik, A F; el-Kersh, T A; Shibl, A M

    1995-02-01

    The effect of subinhibitory concentrations of ciprofloxacin, lomefloxacin, norfloxacin, ofloxacin, and sparfloxacin on urease activity and on cell surface hydrophobicity of urea-splitting bacteria was examined. Quinolones at 0.5 MICs demonstrated variable effects on bacterial-urease activity. Norfloxacin inhibited enzyme activity in Proteus vulgaris and Proteus mirabilis, while other quinolones had no effects. In Morganella morganii, sparfloxacin and ciprofloxacin enhanced urease activity, particularly at the initial phase of growth. All quinolones tested showed no marked effect on urease activity by Providencia rettgeri. Quinolones at the same concentrations induced an increase in the cell surface hydrophobicity, which was strain-dependent. There was no correlation between urease inhibition and cell surface hydrophobicity. Inhibition of urease activity by quinolones, in addition to their antibacterial activities, may prevent the progression of urinary tissue damage and stone formation. PMID:7844396

  14. Two approaches to form antibacterial surface: Doping with bactericidal element and drug loading

    NASA Astrophysics Data System (ADS)

    Sukhorukova, I. V.; Sheveyko, A. N.; Kiryukhantsev-Korneev, Ph. V.; Anisimova, N. Y.; Gloushankova, N. A.; Zhitnyak, I. Y.; Benesova, J.; Amler, E.; Shtansky, D. V.

    2015-03-01

    Two approaches (surface doping with bactericidal element and loading of antibiotic into specially formed surface microcontainers) to the fabrication of antibacterial yet biocompatible and bioactive surfaces are described. A network structure with square-shaped blind pores of 2.6 ± 0.6 × 10-3 mm3 for drug loading was obtained by selective laser sintering (SLS). The SLS-fabricated samples were loaded with 0.03, 0.3, 2.4, and 4 mg/cm2 of co-amoxiclav (amoxicillin and clavulanic acid). Ag-doped TiCaPCON films with 0.4, 1.2, and 4.0 at.% of Ag were obtained by co-sputtering of composite TiC0.5-Ca3(PO4)2 and metallic Ag targets. The surface structure of SLS-prepared samples and cross-sectional morphology of TiCaPCON-Ag films were studied by scanning electron microscopy. The through-thickness of Ag distribution in the TiCaPCON-Ag films was obtained by glow discharge optical emission spectroscopy. The kinetics of Ag ion release in normal saline solution was studied using inductively coupled plasma mass spectrometry. Bacterial activity of the samples was evaluated against S. epidermidis, S. aureus, and K. pneum. ozaenae using the agar diffusion test and photometric method by controlling the variation of optical density of the bacterial suspension over time. Cytocompatibility of the Ag-doped TiCaPCON films was observed in vitro using chondrocytic and MC3T3-E1 osteoblastic cells. The viability and proliferation of chondrocytic cells were determined using the MTS assay and PicoGreen assay tests, respectively. The alkaline phosphatase (ALP) activity of the SLS-fabricated samples loaded with co-amoxiclav was also studied. The obtained results showed that the moderate bacteriostatic effect of the Ag-doped TiCaPCON films is mainly manifested in the change of bacterial colony morphology and optical densities of bacteria suspensions. In contrast, the SLS-prepared samples showed a very rapid initial drug release resulting in strong bactericidal effect just from the start of the test and for as long as several days. Cytocompatibility and ALP activity tests demonstrated that it is possible to achieve a pronounced antibacterial effect compatible or even higher than that in the control sample (standard disk loaded with the amoxicillin/clavulanic acid mixture (30 μg)) without compromising the material biocompatibility and bioactivity.

  15. Alkaloids: an overview of their antibacterial, antibiotic-enhancing and antivirulence activities.

    PubMed

    Cushnie, T P Tim; Cushnie, Benjamart; Lamb, Andrew J

    2014-11-01

    With reports of pandrug-resistant bacteria causing untreatable infections, the need for new antibacterial therapies is more pressing than ever. Alkaloids are a large and structurally diverse group of compounds that have served as scaffolds for important antibacterial drugs such as metronidazole and the quinolones. In this review, we highlight other alkaloids with development potential. Natural, semisynthetic and synthetic alkaloids of all classes are considered, looking first at those with direct antibacterial activity and those with antibiotic-enhancing activity. Potent examples include CJ-13,136, a novel actinomycete-derived quinolone alkaloid with a minimum inhibitory concentration of 0.1 ng/mL against Helicobacter pylori, and squalamine, a polyamine alkaloid from the dogfish shark that renders Gram-negative pathogens 16- to >32-fold more susceptible to ciprofloxacin. Where available, information on toxicity, structure-activity relationships, mechanisms of action and in vivo activity is presented. The effects of alkaloids on virulence gene regulatory systems such as quorum sensing and virulence factors such as sortases, adhesins and secretion systems are also described. The synthetic isoquinoline alkaloid virstatin, for example, inhibits the transcriptional regulator ToxT in Vibrio cholerae, preventing expression of cholera toxin and fimbriae and conferring in vivo protection against intestinal colonisation. The review concludes with implications and limitations of the described research and directions for future research. PMID:25130096

  16. Immobilisation of an antibacterial drug to Ti6Al4V components fabricated using selective laser melting

    NASA Astrophysics Data System (ADS)

    Vaithilingam, Jayasheelan; Kilsby, Samuel; Goodridge, Ruth D.; Christie, Steven D. R.; Edmondson, Steve; Hague, Richard J. M.

    2014-09-01

    Bacterial infections from biomedical implants and surgical devices are a major problem in orthopaedic, dental and vascular surgery. Although the sources of contaminations that lead to bacterial infections are known, it is not possible to control or avoid such infections completely. In this study, an approach to immobilise Ciprofloxacin® (an antibacterial drug) to phosphonic acid based self-assembled monolayers (SAMs) adsorbed on a selectively laser melted (SLM) Ti6Al4V structure, has been presented. X-ray photoelectron spectroscopy (XPS) and static water contact angle measurements confirmed the attachment of SAMs and the drug. Results showed that Ciprofloxacin® is highly stable under the oxidative conditions used in this study. In-vitro stability was estimated by immersing the Ciprofloxacin® immobilised substrates in 10 mM of Tris-HCl buffer (pH-7.4) for 42 days. The Tris-HCl buffer was analysed using UV-vis spectrophotometry at 7, 14, 28 and 42 day time intervals to determine the release of the immobilised drug. The drug was observed to release in a sustained manner. 50% of the drug was released after 4 weeks with approximately 40% of the drug remaining after 6 weeks. Antibacterial susceptibility tests revealed that the immobilised drug was therapeutically active upon its release. This study demonstrates the potential to use self-assembled monolayers to modify SLM fabricated surfaces with therapeutics.

  17. Proteomics Evidence for the Activity of the Putative Antibacterial Plant Alkaloid (-)-Roemerine: Mainstreaming Omics-Guided Drug Discovery.

    PubMed

    Gokgoz, Nilay Budeyri; Akbulut, Berna Sariyar

    2015-08-01

    Discovery of new antibacterials with novel mechanisms is important to counteract the ingenious resistance mechanisms of bacteria. In this connection, omics-guided drug discovery offers a rigorous method in the quest of new antibacterials. (-)-Roemerine is a plant alkaloid that has been reported to possess putative antibacterial activity against Escherichia coli, Bacillus subtilis, and Salmonella typhimurium. The aim of the present study was to characterize the activity of (-)-roemerine in Escherichia coli TB1 using proteomics tools. With (-)-roemerine treatment, we found limited permeability through the outer membrane and repression of transport proteins involved in carbohydrate metabolism, resulting in poor carbon source availability. The shortfall of intracellular carbon sources in turn led to impaired cell growth. The reduction in the abundance of proteins related to translational machinery, amino acid biosynthesis, and metabolism was accompanied by a nutrient-limited state. The latter finding could suggest a metabolic shutdown in E. coli cells. High osmolarity was clearly not one of the reasons of bacterial death by (-)-roemerine. These observations collectively attest to the promise of plant omics and profiling of putative drug candidates using proteomics tools. Omics-guided drug discovery deserves greater attention in mainstream pharmacology so as to better understand the plants' medicinal potentials. PMID:26230533

  18. Plasmid-mediated quinolone resistance

    PubMed Central

    Jacoby, George A.; Strahilevitz, Jacob; Hooper, David C.

    2014-01-01

    Summary Three mechanisms for plasmid-mediated quinolone resistance (PMQR) have been discovered since 1998. Plasmid genes qnrA, qnrB, qnrC, qnrD, qnrS, and qnrVC code for proteins of the pentapeptide repeat family that protects DNA gyrase and topoisomerase IV from quinolone inhibition. The qnr genes appear to have been acquired from chromosomal genes in aquatic bacteria, are usually associated with mobilizing or transposable elements on plasmids, and are often incorporated into sul1-type integrons. The second plasmid-mediated mechanism involves acetylation of quinolones with an appropriate amino nitrogen target by a variant of the common aminoglycoside acetyltransferase AAC(6′)-Ib. The third mechanism is enhanced efflux produced by plasmid genes for pumps QepAB and OqxAB. PMQR has been found in clinical and environmental isolates around the world and appears to be spreading. The plasmid-mediated mechanisms provide only low-level resistance that by itself does not exceed the clinical breakpoint for susceptibility but nonetheless facilitates selection of higher-level resistance and makes infection by pathogens containing PMQR harder to treat. PMID:25584197

  19. Investigations into the Antibacterial Activity of the Silver-Based Antibiotic Drug Candidate SBC3

    PubMed Central

    Sharkey, Michael A.; O’Gara, James P.; Gordon, Stephen V.; Hackenberg, Frauke; Healy, Claire; Paradisi, Francesca; Patil, Siddappa; Schaible, Bettina; Tacke, Matthias

    2012-01-01

    The synthesis of N-heterocyclic carbene (NHC) silver(I) acetate complexes with varying lipophilic benzyl-substituents at the 1 and 3 positions starting from 4,5-diphenylimidazole, opened a new class of antibiotic drug candidates. These NHC-silver(I) acetate derivatives exhibit interesting structural motifs in the solid state and proved to be soluble and stable in biological media. The leading candidate, SBC3, which was known to exhibit good antibacterial activity in preliminary Kirby-Bauer tests, was tested quantitatively using minimum inhibitory concentrations. NHC-silver(I) acetate complexes were found to have MIC values ranging from 20 to 3.13 μg/mL for a variety of Gram-positive, Gram-negative and mycobacteria tested. These values represent good antibiotic activities against potential pathogens when compared to clinically approved antibiotics. Most striking is the fact that SBC3 is active against methicillin-resistant Staphylococcus aureus with a MIC value of 12.5 μg/mL.

  20. Clinical Importance and Epidemiology of Quinolone Resistance

    PubMed Central

    Kim, Eu Suk

    2014-01-01

    The quinolone class of antimicrobial agents is one of most widely used classes of antimicrobial agents in outpatient and inpatient treatment. However, quinolone resistance in gram-positive and gram-negative bacteria has emerged and increased globally. This resistance limits the usefulness of quinolones in clinical practice. The review summarizes mechanisms of quinolone resistance and its epidemiology and implications in the most common clinical settings, urinary tract infections, respiratory tract infections, intraabdominal infections, skin and skin structure infections, and sexually transmitted diseases. PMID:25566402

  1. In Vitro Activity of Ozenoxacin against Quinolone-Susceptible and Quinolone-Resistant Gram-Positive Bacteria

    PubMed Central

    Lpez, Y.; Tato, M.; Espinal, P.; Garcia-Alonso, F.; Gargallo-Viola, D.; Cantn, R.

    2013-01-01

    In vitro activity of ozenoxacin, a novel nonfluorinated topical (L. D. Saravolatz and J. Leggett, Clin. Infect. Dis. 37:12101215, 2003) quinolone, was compared with the activities of other quinolones against well-characterized quinolone-susceptible and quinolone-resistant Gram-positive bacteria. Ozenoxacin was 3-fold to 321-fold more active than other quinolones. Ozenoxacin could represent a first-in-class nonfluorinated quinolone for the topical treatment of a broad range of dermatological infections. PMID:24080666

  2. Antibacterial activity of herbal extracts against multi-drug resistant Escherichia coli recovered from retail chicken meat.

    PubMed

    Shaheen, Arfat Yousaf; Sheikh, Ali Ahmad; Rabbani, Masood; Aslam, Asim; Bibi, Tasra; Liaqat, Fakhra; Muhammad, Javed; Rehmani, Shafqat Fatima

    2015-07-01

    Increasing incidence rate of multiple drug resistance in Escherichia coli (E. coli) due to extensive uses of antibiotics is a serious challenge to disease treatment. Contaminated retail chicken meat is one of the major sources of spread of multi drug resistant (MDR) E. coli. Current study has been conducted to study the prevalence of MDR E. coli in retail chicken meat samples from Lahore city of Pakistan and it was found that 73.86% of E. coli isolates have MDR pattern. In vitro evaluation of antibacterial activity of crude ethanolic extracts of six herbs against MDR E. coli phenotypes has revealed that clove and cinnamon have maximum zones of inhibition as compared to other herbal extracts. Mint and coriander gave the intermediate results while garlic and kalonji showed the least antibacterial activity against the MDR E. coli phenotypes using the agar well diffusion technique. Average Minimum Inhibitory Concentrations (MICs) for clove, mint, cinnamon, coriander, kalonji and garlic extracts were 1.15, 1.38, 0.5, 1.99, 2.41, 8.60 mg/mL respectively using the broth micro dilution method. The results obtained in present study were revealed that crude ethanol extracts of selected herbs have had significant antibacterial activity. Hence they can be used as promising alternatives of antimicrobials against MDR E. coli species and can be used for cooked food preservation. PMID:26142503

  3. Surveillance of the overall consumption of antibacterial drugs in humans, domestic animals and farmed fish in Norway in 1992 and 1996.

    PubMed

    Grave, K; Lingaas, E; Bangen, M; Rønning, M

    1999-02-01

    The annual overall consumption of antibacterial drugs in Norway, categorized into human use, use in domestic animals and in farmed fish, was estimated from wholesaler and feed-mill sales statistics. Comprehensive data on drug consumption in human medicine in Norway are published on a regular basis on behalf of the drug authorities. These data, including use of antibacterial drugs, are expressed as the number of defined daily doses (DDD)/1000 inhabitants/year. DDD cannot be employed to compare antibiotic consumption in human and veterinary medicine as it is possible to calculate such data for only a few veterinary drugs. The only parameter for which data are generally available, so far, is the amount used in kilograms of active substance, which is the unit of measurement chosen in this study. It was found that annual overall sales of antibacterial drugs in Norway, including antibacterial and ionophore feed additives, decreased from 77 tonnes in 1992 to 49 tonnes in 1996, a 37% reduction. The use in 1996 in human medicine, animals and farmed fish was 35 tonnes, 13 tonnes and 1 tonne, respectively. While the annual amounts used in human medicine remained unchanged from 1992 to 1996, therapeutic use in fish farming declined by 96%. In domestic animals, therapeutic use and use as feed additives declined by 17% and 5%, respectively. During the study period, the size of the human and domestic animal populations at risk remained almost constant, while the biomass (weight) of farmed fish at risk increased by > 100%. This implies that both the absolute and relative consumption of antibacterial drugs in Norway decreased substantially during the study period. The use of antibacterial drugs, both in humans and in domestic animals, has changed in favour of penicillins, this being in accordance with general recommendations. The reduction in the use of antibacterial drugs in farmed fish has been almost solely due to the introduction of oil-adjuvanted vaccines against furuncolosis. It is concluded that the decline in the amount of antibacterial drugs used in domestic animals, and the changes with regard to choice of drugs, could be mainly attributed to changes in prescribing behaviour following advice and recommendations. Moreover, the overall use of antibacterial drugs in Norway is very low compared with that in most other countries and has been significantly reduced during the 1990s. PMID:11252330

  4. Evaluating the impact of a novel restricted reimbursement policy for quinolone antibiotics: A time series analysis

    PubMed Central

    2012-01-01

    Background Publicly-funded drug plans often use prior authorization policies to limit drug prescribing. To guide physician prescribing of a class of antibiotics with broad antimicrobial activity (quinolone antibiotics) in accordance with new prescribing guidelines, Albertas provincial health ministry implemented a new mechanism for formulary restriction entitled the optional special authorization (OSA) program. We conducted an observational study to determine the impact of this new formulary restriction policy on antimicrobial prescription rates as well as any clinical consequences. Methods Quinolone antibiotic use, and adherence with quinolone prescribing guidelines, was assessed before and after implementation of the OSA program in patients with common outpatient infections using an administrative data cohort and a chart review cohort, respectively. At the same time this policy was implemented to limit quinolone prescribing, two new quinolone antibiotics were added to the formulary. Using administrative data, we analysed a total of 397,534 unique index visits with regard to overall antibiotic utilization, and through chart review, we analysed 1681 charts of patients with infections of interest to determine the indications for quinolone usage. Results Using segmented regression models adjusting for age, sex and physician enrollment in the OSA program, there was no statistically significant change in the monthly rate of all quinolone use (?3.5 (95% CI ?5.5, 1.4) prescriptions per 1000 index visits) following implementation of the OSA program (p?=?0.74). There was a significant level change in the rate of quinolone antibiotic use for urinary tract infection (?33.6 (95% CI: -23.8, -43.4) prescriptions and upper respiratory tract infection (?16.1 (95%CI: -11.6, -20.6) prescriptions per 1000 index visits. Among quinolone prescriptions identified on chart review, 42.5% and 58.5% were consistent with formulary guidelines before and after the implementation of the OSA program, respectively (p?=?0.002). There was no change in hospitalization, mortality or use of physician services after implementation of the OSA program. Conclusions Despite the addition of two new quinolone antibiotics to the formulary, we found that there was no change in the use of quinolones after implementation of a new formulary restriction policy for outpatients with common outpatient infections. PMID:22935100

  5. [Looking for the new preparations for antibacterial therapy. I. New antibiotics and chemotherapeutics on the market].

    PubMed

    Karpiuk, Izabela; Tyski, Stefan

    2012-01-01

    Development of new mechanisms of resistance and relatively easy and fast transferring of resistance genes between cells have resulted in emergence of large number of multi-drug resistant bacteria in recent years. Therefore, it is important to intensively search for new, effective compounds possessing antibacterial potential and apply them as active ingredients of medicinal products. This procedure may lead to eradication of clinically relevant, dangerous bacteria. In the twentyfirst century, three new classes of antibacterial agents: oxazolidinones, lipopeptides and pleuromutilins were introduced into the therapy. Compounds from the last group, such as tiamulin, were used previously, but only in veterinary. New 18 antimicrobial compounds, belonging to known therapeutic groups, have been registered since 2000. The largest group among antibacterial chemotherapeutics is quinolones. Group of natural compounds includes: new carbapenems, cephalosporins of V generation and other agents, like telithromycin, tigecycline, telavancin and fidaxomicin. This article is a part of the series associated with searching for new antibacterial agents and it relates to new antibiotics and antibacterial chemotherapeutics approved for the world-wide market since 2000. The next parts of this cycle will be devoted to compounds ongoing the clinical trials. PMID:23484382

  6. Laser receptive polyelectrolyte thin films doped with biosynthesized silver nanoparticles for antibacterial coatings and drug delivery applications.

    PubMed

    Sripriya, Jaganathan; Anandhakumar, Sundaramurthy; Achiraman, Shanmugam; Antony, Jacob Joe; Siva, Durairaj; Raichur, Ashok M

    2013-11-30

    We report a simple method to fabricate multifunctional polyelectrolyte thin films to load and deliver the therapeutic drugs. The multilayer thin films were assembled by the electrostatic adsorption of poly (allylamine hydrochloride) (PAH) and dextran sulfate (DS). The silver nanoparticles (Ag NPs) biosynthesized from novel Hybanthus enneaspermus leaf extract as the reducing agent were successfully incorporated into the film. The biosynthesized Ag NPs showed excellent antimicrobial activity against the range of enteropathogens, which could be significantly enhanced when used with commercial antibiotics. The assembled silver nano composite multilayer films showed rupture and deformation when they are exposed to laser. The Ag NPs act as an energy absorption center, locally heat up the film and rupture it under laser treatment. The antibacterial drug, moxifloxacin hydrochloride (MH) was successfully loaded into the multilayer films. The total amount of MH release observed was about 63% which increased to 85% when subjected to laser light exposure. Thus, the polyelectrolyte thin film reported in our study has significant potential in the field of remote activated drug delivery, antibacterial coatings and wound dressings. PMID:24096301

  7. Putative histidine kinase inhibitors with antibacterial effect against multi-drug resistant clinical isolates identified by in vitro and in silico screens

    PubMed Central

    Velikova, Nadya; Fulle, Simone; Manso, Ana Sousa; Mechkarska, Milena; Finn, Paul; Conlon, J. Michael; Oggioni, Marco Rinaldo; Wells, Jerry M.; Marina, Alberto

    2016-01-01

    Novel antibacterials are urgently needed to address the growing problem of bacterial resistance to conventional antibiotics. Two-component systems (TCS) are widely used by bacteria to regulate gene expression in response to various environmental stimuli and physiological stress and have been previously proposed as promising antibacterial targets. TCS consist of a sensor histidine kinase (HK) and an effector response regulator. The HK component contains a highly conserved ATP-binding site that is considered to be a promising target for broad-spectrum antibacterial drugs. Here, we describe the identification of putative HK autophosphorylation inhibitors following two independent experimental approaches: in vitro fragment-based screen via differential scanning fluorimetry and in silico structure-based screening, each followed up by the exploration of analogue compounds as identified by ligand-based similarity searches. Nine of the tested compounds showed antibacterial effect against multi-drug resistant clinical isolates of bacterial pathogens and include three novel scaffolds, which have not been explored so far in other antibacterial compounds. Overall, putative HK autophosphorylation inhibitors were found that together provide a promising starting point for further optimization as antibacterials. PMID:27173778

  8. Putative histidine kinase inhibitors with antibacterial effect against multi-drug resistant clinical isolates identified by in vitro and in silico screens.

    PubMed

    Velikova, Nadya; Fulle, Simone; Manso, Ana Sousa; Mechkarska, Milena; Finn, Paul; Conlon, J Michael; Oggioni, Marco Rinaldo; Wells, Jerry M; Marina, Alberto

    2016-01-01

    Novel antibacterials are urgently needed to address the growing problem of bacterial resistance to conventional antibiotics. Two-component systems (TCS) are widely used by bacteria to regulate gene expression in response to various environmental stimuli and physiological stress and have been previously proposed as promising antibacterial targets. TCS consist of a sensor histidine kinase (HK) and an effector response regulator. The HK component contains a highly conserved ATP-binding site that is considered to be a promising target for broad-spectrum antibacterial drugs. Here, we describe the identification of putative HK autophosphorylation inhibitors following two independent experimental approaches: in vitro fragment-based screen via differential scanning fluorimetry and in silico structure-based screening, each followed up by the exploration of analogue compounds as identified by ligand-based similarity searches. Nine of the tested compounds showed antibacterial effect against multi-drug resistant clinical isolates of bacterial pathogens and include three novel scaffolds, which have not been explored so far in other antibacterial compounds. Overall, putative HK autophosphorylation inhibitors were found that together provide a promising starting point for further optimization as antibacterials. PMID:27173778

  9. Antibacterial activities of Beilschmiedia obscura and six other Cameroonian medicinal plants against multi-drug resistant Gram-negative phenotypes

    PubMed Central

    2014-01-01

    Background The rapid spread of bacteria expressing multi-drug resistance propels the search for new antibacterial agents. The present study was designed to evaluate the antibacterial activities of the methanol extracts from Beilschmiedia obscura and six other Cameroonian plants against a panel of twenty nine Gram-negative bacteria including Multi-drug resistant (MDR) phenotypes. Methods The phytochemical investigations of the extracts were carried out according to the standard methods and the liquid micro-dilution assay was used for all antibacterial assays. Results Phytochemical analysis showed the presence of alkaloids in all studied extracts. Other chemical classes of secondary metabolites such as anthocyanines, anthraquinones flavonoids, saponins, tannins, sterols and triterpenes were selectively detected in the extracts. The extract from the fruits of Beilschmiedia obscura, Pachypodanthium staudtii leaves and Peperomia fernandopoiana (whole plant) displayed the best spectrum of activity with MIC values ranging from 16 to 1024 μg/mL against at least 65% and above of the tested bacteria. The extract from Beilschmiedia obscura was the most active with MIC values below 100 μg/mL against ten of the tested bacteria. This extract also showed MBC values below 1024 μg/mL against 55.17% of the studied microorganisms. Phenylalanine arginine β-naphthylamide (PAβN) significantly modulated the activities of extracts from the leaves and fruits of Pachypodanthium staudtii and Beilschmiedia obscura respectively, by increasing their inhibitory activity against Klebsiella pneumoniae KP55 strain at least four fold. Conclusion The overall results of the present investigation provide information for the possible use of the methanol extracts of the studied plant species, especially B. obscura to fight infectious diseases caused by Gram-negative bacteria including MDR phenotypes. PMID:25023038

  10. ATP-Bound Conformation of Topoisomerase IV: a Possible Target for Quinolones in Streptococcus pneumoniae

    PubMed Central

    Sifaoui, Farid; Lamour, Valérie; Varon, Emmanuelle; Moras, Dino; Gutmann, Laurent

    2003-01-01

    Topoisomerase IV, a C2E2 tetramer, is involved in the topological changes of DNA during replication. This enzyme is the target of antibacterial compounds, such as the coumarins, which target the ATP binding site in the ParE subunit, and the quinolones, which bind, outside the active site, to the quinolone resistance-determining region (QRDR). After site-directed and random mutagenesis, we found some mutations in the ATP binding site of ParE near the dimeric interface and outside the QRDR that conferred quinolone resistance to Streptococcus pneumoniae, a bacterial pathogen. Modeling of the N-terminal, 43-kDa ParE domain of S. pneumoniae revealed that the most frequent mutations affected conserved residues, among them His43 and His103, which are involved in the hydrogen bond network supporting ATP hydrolysis, and Met31, at the dimeric interface. All mutants showed a particular phenotype of resistance to fluoroquinolones and an increase in susceptibility to novobiocin. All mutations in ParE resulted in resistance only when associated with a mutation in the QRDR of the GyrA subunit. Our models of the closed and open conformations of the active site indicate that quinolones preferentially target topoisomerase IV of S. pneumoniae in its ATP-bound closed conformation. PMID:14526026

  11. Synthesis and Characterization of Potential Dimers of Gatifloxacin – an Antibacterial Drug

    PubMed Central

    Garaga, Srinivas; Raghava Reddy, Ambati V.; Prabahar, Koilpillai Joseph; Korupolu, Raghu Babu; Sanasi, Paul Douglas

    2013-01-01

    Gatifloxacin is an antibacterial agent belonging to the fourth-generation fluoroquinolone family. Four piperazine-linked fluoroquinolone dimers of Gatifloxacin were observed during the laboratory process for Gatifloxacin and they were identified. The present work describes the origin, synthesis, characterization, and control of these dimers along with the synthesis of Despropylene Gatifloxacin (metabolite). PMID:24106664

  12. Lead Optimization of 3-Carboxyl-4(1H)-Quinolones to Deliver Orally Bioavailable Antimalarials

    PubMed Central

    Zhang, Yiqun; Clark, Julie A; Connelly, Michele C.; Zhu, Fangyi; Min, Jaeki; Guiguemde, W. Armand; Pradhan, Anupam; Iyer, Lalitha; Furimsky, Anna; Gow, Jason; Parman, Toufan; El Mazouni, Farah; Phillips, Margaret A.; Kyle, Dennis E.; Mirsalis, Jon; Guy, R. Kiplin

    2012-01-01

    Malaria is a protozoal parasitic disease that is widespread in tropical and subtropical regions of Africa, Asia, and the Americas and causes more than 800,000 deaths per year. The continuing emergence of multi-drug-resistant Plasmodium falciparum drives the ongoing need for the development of new and effective antimalarial drugs. Our previous work has explored the preliminary structural optimization of 4(1H)-quinolone ester derivatives, a new series of antimalarials related to the endochins. Herein, we report the lead optimization of 4(1H)-quinolones with a focus on improving both antimalarial potency and bioavailability. These studies led to the development of orally efficacious antimalarials including quinolone analogue 20g, a promising candidate for further optimization. PMID:22435599

  13. Relationships among antibacterial activity, inhibition of DNA gyrase, and intracellular accumulation of 11 fluoroquinolones.

    PubMed Central

    Bazile, S; Moreau, N; Bouzard, D; Essiz, M

    1992-01-01

    A series of 11 fluoroquinolone antibacterial agents, including 8 newly synthesized molecules and 3 reference compounds (pefloxacin, ciprofloxacin, and sparfloxacin), were tested for their MICs against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. The intracellular accumulation of fluoroquinolones by these microorganisms was measured by centrifugation through silicone oil and a fluorescence assay. The minimal effective dose (MED) was determined for all agents in a supercoiling assay with E. coli DNA gyrase. The hydrophobicities of the quinolones were determined and expressed as the logarithm of the coefficient of distribution (log D) between 1-octanol and phosphate buffer (pH 7.2). No correlation was found between MICs and cell accumulation for the quinolones studied. A correlation was found between log D and accumulation by S. aureus (r = 0.71, n = 11), and an inverse correlation was found between log D and accumulation by E. coli (r = 0.73, n = 11) and P. aeruginosa (r = 0.64, n = 10). The correlation coefficients between MICs and MED for E. coli, which were 0.60, 0.64, and 0.74 (n = 11) for E. coli, P. aeruginosa, and S. aureus, respectively, rose to 0.85, 0.74, and 0.74 (n = 11) for the same microorganisms, respectively, when the accumulation of the drug by the cell was taken into account. It was concluded that the inhibitory activity against DNA gyrase remains the most important parameter for quinolone potency, but that intracellular accumulation must be taken into account, since, for a given organism, both parameters are under the control of the physicochemical properties of the quinolones. PMID:1336340

  14. Proteomic response of methicillin-resistant S. aureus to a synergistic antibacterial drug combination: a novel erythromycin derivative and oxacillin.

    PubMed

    Liu, Xiaofen; Pai, Pei-Jin; Zhang, Weipeng; Hu, Yingwei; Dong, Xiaojing; Qian, Pei-yuan; Chen, Daijie; Lam, Henry

    2016-01-01

    The use of antibacterial drug combinations with synergistic effects is increasingly seen as a critical strategy to combat multi-drug resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). In this work, the proteome responses in MRSA under the stress of a sub-inhibitory dose of a synergistic drug combination of a novel erythromycin derivative, SIPI-8294, and oxacillin, were studied by label-free quantitative proteomics. Several control treatment groups were designed to isolate proteome responses potentially related to the synergy: (1) the non-synergistic drug combination of erythromycin and oxacillin, (2) SIPI-8294 only, (3) oxacillin only and (4) erythromycin only. Results showed that 200 proteins were differentially expressed in SIPI-8294/oxacillin-treated cells. Among these proteins, the level of penicillin binding protein 2a, the protein mainly responsible for oxacillin resistance in MRSA, was four times lower in the SIPI-8294/oxacillin group than in the erythromycin/oxacillin group, suggesting that SIPI-8294 may interfere with this known oxacillin resistance mechanism. Moreover, hierarchical clustering analysis of differentially expressed proteins under different treatments revealed that SIPI-8294/oxacillin elicits very different responses than the individual drugs or the non-synergistic erythromycin/oxacillin combination. Bioinformatic analysis indicated that the synergistic effect can be further traced to a disruption in oxidation-reduction homeostasis and cell wall biosynthesis. PMID:26806358

  15. Proteomic response of methicillin-resistant S. aureus to a synergistic antibacterial drug combination: a novel erythromycin derivative and oxacillin

    PubMed Central

    Liu, Xiaofen; Pai, Pei-Jin; Zhang, Weipeng; Hu, Yingwei; Dong, Xiaojing; Qian, Pei-yuan; Chen, Daijie; Lam, Henry

    2016-01-01

    The use of antibacterial drug combinations with synergistic effects is increasingly seen as a critical strategy to combat multi-drug resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). In this work, the proteome responses in MRSA under the stress of a sub-inhibitory dose of a synergistic drug combination of a novel erythromycin derivative, SIPI-8294, and oxacillin, were studied by label-free quantitative proteomics. Several control treatment groups were designed to isolate proteome responses potentially related to the synergy: (1) the non-synergistic drug combination of erythromycin and oxacillin, (2) SIPI-8294 only, (3) oxacillin only and (4) erythromycin only. Results showed that 200 proteins were differentially expressed in SIPI-8294/oxacillin-treated cells. Among these proteins, the level of penicillin binding protein 2a, the protein mainly responsible for oxacillin resistance in MRSA, was four times lower in the SIPI-8294/oxacillin group than in the erythromycin/oxacillin group, suggesting that SIPI-8294 may interfere with this known oxacillin resistance mechanism. Moreover, hierarchical clustering analysis of differentially expressed proteins under different treatments revealed that SIPI-8294/oxacillin elicits very different responses than the individual drugs or the non-synergistic erythromycin/oxacillin combination. Bioinformatic analysis indicated that the synergistic effect can be further traced to a disruption in oxidation-reduction homeostasis and cell wall biosynthesis. PMID:26806358

  16. Fabrication of chitosan-g-poly(acrylamide)/CuS nanocomposite for controlled drug delivery and antibacterial activity.

    PubMed

    Pathania, Deepak; Gupta, Divya; Agarwal, Shilpi; Asif, M; Gupta, Vinod Kumar

    2016-07-01

    In present study, we reported the synthesis of chitosan-g-poly(acrylamide)/CuS (CPA/CS) nanocomposite for controlled delivery of ofloxacin. The CPA/CS nanocomposites were characterized by Fourier transmission infrared spectroscopy (FTIR), UV-visible spectroscopy (UV), scanning electron microscopy (SEM), X-ray diffraction (XRD) analysis. From the FTIR spectra, the various groups present in CPA/CS nanocomposite were monitored. The homogeneity, morphology and crystallinity of the CPA/CS nanocomposite were ascertained from SEM/EDX and XRD data, respectively. The kinetics of ofloxacin drug delivery was investigated at different pH. The drug released studies were investigated at different pH (2.2, 7.4 and 9.4) and time intervals (2, 4, 6, 8, 10, 12, 14, 16h). The drug release behavior depends upon the pH of medium and the nature of matrix. The maximum drug loading efficiency of 85% was recorded for CPA/CS. The maximum drug release of 76% was observed at 2.2. pH after 18h onto CPA/CS. Nanocomposites were also tested for antibacterial activity against Escherichia coli bacteria. About 97% killing of E. coli was observed after 24h. PMID:27127073

  17. Role of the Water–Metal Ion Bridge in Mediating Interactions between Quinolones and Escherichia coli Topoisomerase IV

    PubMed Central

    2015-01-01

    Although quinolones have been in clinical use for decades, the mechanism underlying drug activity and resistance has remained elusive. However, recent studies indicate that clinically relevant quinolones interact with Bacillus anthracis (Gram-positive) topoisomerase IV through a critical water–metal ion bridge and that the most common quinolone resistance mutations decrease drug activity by disrupting this bridge. As a first step toward determining whether the water–metal ion bridge is a general mechanism of quinolone–topoisomerase interaction, we characterized drug interactions with wild-type Escherichia coli (Gram-negative) topoisomerase IV and a series of ParC enzymes with mutations (S80L, S80I, S80F, and E84K) in the predicted bridge-anchoring residues. Results strongly suggest that the water–metal ion bridge is essential for quinolone activity against E. coli topoisomerase IV. Although the bridge represents a common and critical mechanism that underlies broad-spectrum quinolone function, it appears to play different roles in B. anthracis and E. coli topoisomerase IV. The water–metal ion bridge is the most important binding contact of clinically relevant quinolones with the Gram-positive enzyme. However, it primarily acts to properly align clinically relevant quinolones with E. coli topoisomerase IV. Finally, even though ciprofloxacin is unable to increase levels of DNA cleavage mediated by several of the Ser80 and Glu84 mutant E. coli enzymes, the drug still retains the ability to inhibit the overall catalytic activity of these topoisomerase IV proteins. Inhibition parallels drug binding, suggesting that the presence of the drug in the active site is sufficient to diminish DNA relaxation rates. PMID:25115926

  18. Prophylactic use of the new quinolones for prevention of nosocomial infection in the intensive care unit.

    PubMed

    Potgieter, P D; Hammond, J M

    1995-01-01

    The new quinolone antimicrobial agents, particularly those with less activity against anaerobes, selectively prevent colonisation of the alimentary tract by Gram-negative bacilli and staphylococci without substantially affecting the normal anaerobic flora, which preserve the colonisation resistance of the gut. These properties ideally position this class of antibacterial agent for selective decontamination of the digestive tract (SDD) in the prevention of nosocomial infection. The rationale for this procedure is based on the presumption that a significant proportion of infections in compromised patients are endogenous in origin, arising from the host's own microbial flora. If this colonisation by potentially pathogenic microflora within the normal flora can be significantly reduced without being replaced by other more pathogenic microorganisms, the risk of endogenous infection should be minimised. The quinolones have proved to be ideal agents for use in preventing infection in bone marrow transplant and other neutropenic patients. They have been used for SDD in the general intensive care unit population, although the technique has not received widespread acceptance. There have been only 4 reported randomised studies using quinolones as part of SDD regimens and only 301 patients have been evaluated. Although the incidence of ventilator-associated pneumonia has been significantly reduced from 36 to 15%, no effect has been shown on mortality. The cost of using SDD is significantly less with the quinolones than with other regimens, and induction of resistance has not been noted. The new quinolones, and in particular the more recently developed agents with extended Gram-positive activity, appear to be ideally suited for SDD, and their careful evaluation in further large, well designed trials is warranted. PMID:8549422

  19. Depletion of T cell epitopes in lysostaphin mitigates anti-drug antibody response and enhances antibacterial efficacy in vivo

    PubMed Central

    Zhao, Hongliang; Verma, Deeptak; Li, Wen; Choi, Yoonjoo; Ndong, Christian; Fiering, Steven N.; Bailey-Kellogg, Chris; Griswold, Karl E.

    2015-01-01

    SUMMARY The enzyme lysostaphin possesses potent anti-staphylococcal activity and represents a promising antibacterial drug candidate; however, its immunogenicity poses a barrier to clinical translation. Here, structure-based biomolecular design enabled widespread depletion of lysostaphin’s DRB1*0401 restricted T cell epitopes, and resulting deimmunized variants exhibited striking reductions in anti-drug antibody responses upon administration to humanized HLA-transgenic mice. This reduced immunogenicity translated into improved efficacy in the form of protection against repeated challenges with methicillin-resistant Staphylococcus aureus, or MRSA. In contrast, while wild type lysostaphin was efficacious against the initial MRSA infection, it failed to clear subsequent bacterial challenges that were coincident with escalating anti-drug antibody titers. These results extend the existing deimmunization literature, in which reduced immunogenicity and retained efficacy are assessed independently of each other. By correlating in vivo efficacy with longitudinal measures of anti-drug antibody development, we provide the first direct evidence that T cell epitope depletion manifests enhanced biotherapeutic efficacy. PMID:26000749

  20. Distribution of Quinolones, Sulfonamides, Tetracyclines in Aquatic Environment and Antibiotic Resistance in Indochina

    PubMed Central

    Suzuki, Satoru; Hoa, Phan Thi Phuong

    2012-01-01

    Southeast Asia has become the center of rapid industrial development and economic growth. However, this growth has far outpaced investment in public infrastructure, leading to the unregulated release of many pollutants, including wastewater-related contaminants such as antibiotics. Antibiotics are of major concern because they can easily be released into the environment from numerous sources, and can subsequently induce development of antibiotic-resistant bacteria. Recent studies have shown that for some categories of drugs this source-to-environment antibiotic resistance relationship is more complex. This review summarizes current understanding regarding the presence of quinolones, sulfonamides, and tetracyclines in aquatic environments of Indochina and the prevalence of bacteria resistant to them. Several noteworthy findings are discussed: (1) quinolone contamination and the occurrence of quinolone resistance are not correlated; (2) occurrence of the sul sulfonamide resistance gene varies geographically; and (3) microbial diversity might be related to the rate of oxytetracycline resistance. PMID:22363337

  1. Activity of quinolone CP-115,955 against bacterial and human type II topoisomerases is mediated by different interactions.

    PubMed

    Aldred, Katie J; Schwanz, Heidi A; Li, Gangqin; Williamson, Benjamin H; McPherson, Sylvia A; Turnbough, Charles L; Kerns, Robert J; Osheroff, Neil

    2015-02-10

    CP-115,955 is a quinolone with a 4-hydroxyphenyl at C7 that displays high activity against both bacterial and human type II topoisomerases. To determine the basis for quinolone cross-reactivity between bacterial and human enzymes, the activity of CP-115,955 and a series of related quinolones and quinazolinediones against Bacillus anthracis topoisomerase IV and human topoisomerase IIα was analyzed. Results indicate that the activity of CP-115,955 against the bacterial and human enzymes is mediated by different interactions. On the basis of the decreased activity of quinazolinediones against wild-type and resistant mutant topoisomerase IV and the low activity of quinolones against resistant mutant enzymes, it appears that the primary interaction of CP-115,955 with the bacterial system is mediated through the C3/C4 keto acid and the water-metal ion bridge. In contrast, the drug interacts with the human enzyme primarily through the C7 4-hydroxyphenyl ring and has no requirement for a substituent at C8 in order to attain high activity. Despite the fact that the human type II enzyme is unable to utilize the water-metal ion bridge, quinolones in the CP-115,955 series display higher activity against topoisomerase IIα in vitro and in cultured human cells than the corresponding quinazolinediones. Thus, quinolones may be a viable platform for the development of novel drugs with anticancer potential. PMID:25586498

  2. The Activity of Quinolone CP-115,955 Against Bacterial and Human Type II Topoisomerases Is Mediated by Different Interactions

    PubMed Central

    Aldred, Katie J.; Schwanz, Heidi A.; Li, Gangqin; Williamson, Benjamin H.; McPherson, Sylvia A.; Turnbough, Charles L.; Kerns, Robert J.; Osheroff, Neil

    2015-01-01

    CP-115,955 is a quinolone with a 4-hydroxyphenyl at C7 that displays high activity against both bacterial and human type II topoisomerases. To determine the basis for quinolone cross-reactivity between bacterial and human enzymes, the activity of CP-115,955 and a series of related quinolones and quinazolinediones against Bacillus anthracis topoisomerase IV and human topoisomerase IIα was analyzed. Results indicate that the activity of CP-115,955 against the bacterial and human enzymes is mediated by different interactions. Based on the decreased activity of quinazolinediones against wild-type and resistant mutant topoisomerase IV and the low activity of quinolones against resistant mutant enzymes, it appears that the primary interaction of CP-115,955 with the bacterial system is mediated through the C3/C4 keto acid and the water-metal ion bridge. In contrast, the drug interacts with the human enzyme primarily through the C7 4-hydroxyphenyl ring and has no requirement for a substituent at C8 in order to attain high activity. Despite the fact that the human type II enzyme is unable to utilize the water-metal ion bridge, quinolones in the CP-115,955 series display higher activity against topoisomerase IIα in vitro and in cultured human cells than the corresponding quinazolinediones. Thus, quinolones may be a viable platform for the development of novel drugs with anticancer potential. PMID:25586498

  3. [Sensitivity to antibacterial drugs of Salmonella isolated from various sources in Saint-Petersburg and Leningrad region].

    PubMed

    Kozlova, N S; Ivanov, N S; Kuz'min, V A; Lipatova, L A; Gladin, D P

    1995-03-01

    The position of antibiotic resistant cultures among 1706 strains of 85 Salmonella serovars isolated from various sources in St. Petersburg and the Leningrad Region in 1984-1991 amounted to 16.4 per cent. The highest position of such cultures was among the isolates from humans (20.9 per cent). The positions of the isolates from animals, birds and environment were practically equal (13.8, 13.8 and 13.7 per cent respectively). Strains resistant to streptomycin (11.9 per cent), tetracycline (11.5 per cent) and chloramphenicol (11.2 per cent) were the most frequent Salmonella isolates from the different sources. Rifampicin, amikacin, thienamycin, nitroxolin, oxolinic acid, dioxidin, ciprofloxacin and pefloxacin proved to be highly active against the isolates. No significant difference in the antibiotic resistance spectra of the Salmonella strains circulating in different biotopes was detected. However, among the Salmonella isolates from humans there undoubtedly predominated polyresistant strains with the resistance spectra including 10 and 6 antibacterial drugs (42.4 and 28.8 per cent of the resistant strains respectively). Sometimes there was observed correlation between the serovars of the Salmonella strains (independent of the isolation source) and the most characteristic spectra of their antibiotic resistance. Thus, the antibiotic resistant spectra of 79 per cent of the S. typhimurium strains and 82.5 per cent of the S. haifa strains resistant to one and more antibacterial drugs were the following: CmTcSmKmMmNm and ApCbCmTcSmKmMmNmGmNal respectively. PMID:7575013

  4. MRJP1-containing glycoproteins isolated from honey, a novel antibacterial drug candidate with broad spectrum activity against multi-drug resistant clinical isolates

    PubMed Central

    Brudzynski, Katrina; Sjaarda, Calvin; Lannigan, Robert

    2015-01-01

    The emergence of extended- spectrum β-lactamase (ESBL) is the underlying cause of growing antibiotic resistance among Gram-negative bacteria to β-lactam antibiotics. We recently reported the discovery of honey glycoproteins (glps) that exhibited a rapid, concentration-dependent antibacterial activity against both Gram-positive Bacillus subtilis and Gram-negative Escherichia coli that resembled action of cell wall-active β-lactam drugs. Glps showed sequence identity with the Major Royal Jelly Protein 1 (MRJP1) precursor that harbors three antimicrobial peptides: Jelleins 1, 2, and 4. Here, we used semi-quantitative radial diffusion assay and broth microdilution assay to evaluate susceptibility of a number of multi-drug resistant (MDR) clinical isolates to the MRJP1-contaning honey glycoproteins. The MDR bacterial strains comprised three methicillin-resistant Staphylococcus aureus (MRSA), four Pseudomonas aeruginosa, two Klebsiella pneumoniae, two vancomycin-resistant Enterococci (VRE), and five ESBL identified as one Proteus mirabilis, three E. coli, and one E. coli NDM. Their resistance to different classes of antibiotics was confirmed using automated system Vitek 2. MDR isolates differed in their susceptibility to glps with MIC90 values ranging from 4.8 μg/ml against B. subtilis to 14.4 μg/ml against ESBL K. pneumoniae, Klebsiella spp. ESBL and E. coli and up to 33 μg/ml against highly resistant strains of P. aeruginosa. Glps isolated from different honeys showed a similar ability to overcome bacterial resistance to β-lactams suggesting that (a) their mode of action is distinct from other classes of β-lactams and that (b) the common glps structure was the lead structure responsible for the activity. The results of the current study together with our previous evidence of a rapid bactericidal activity of glps demonstrate that glps possess suitable characteristics to be considered a novel antibacterial drug candidate. PMID:26217333

  5. MRJP1-containing glycoproteins isolated from honey, a novel antibacterial drug candidate with broad spectrum activity against multi-drug resistant clinical isolates.

    PubMed

    Brudzynski, Katrina; Sjaarda, Calvin; Lannigan, Robert

    2015-01-01

    The emergence of extended- spectrum β-lactamase (ESBL) is the underlying cause of growing antibiotic resistance among Gram-negative bacteria to β-lactam antibiotics. We recently reported the discovery of honey glycoproteins (glps) that exhibited a rapid, concentration-dependent antibacterial activity against both Gram-positive Bacillus subtilis and Gram-negative Escherichia coli that resembled action of cell wall-active β-lactam drugs. Glps showed sequence identity with the Major Royal Jelly Protein 1 (MRJP1) precursor that harbors three antimicrobial peptides: Jelleins 1, 2, and 4. Here, we used semi-quantitative radial diffusion assay and broth microdilution assay to evaluate susceptibility of a number of multi-drug resistant (MDR) clinical isolates to the MRJP1-contaning honey glycoproteins. The MDR bacterial strains comprised three methicillin-resistant Staphylococcus aureus (MRSA), four Pseudomonas aeruginosa, two Klebsiella pneumoniae, two vancomycin-resistant Enterococci (VRE), and five ESBL identified as one Proteus mirabilis, three E. coli, and one E. coli NDM. Their resistance to different classes of antibiotics was confirmed using automated system Vitek 2. MDR isolates differed in their susceptibility to glps with MIC90 values ranging from 4.8 μg/ml against B. subtilis to 14.4 μg/ml against ESBL K. pneumoniae, Klebsiella spp. ESBL and E. coli and up to 33 μg/ml against highly resistant strains of P. aeruginosa. Glps isolated from different honeys showed a similar ability to overcome bacterial resistance to β-lactams suggesting that (a) their mode of action is distinct from other classes of β-lactams and that (b) the common glps structure was the lead structure responsible for the activity. The results of the current study together with our previous evidence of a rapid bactericidal activity of glps demonstrate that glps possess suitable characteristics to be considered a novel antibacterial drug candidate. PMID:26217333

  6. Antibacterial therapy of aspiration pneumonia in patients with methicillin-resistant Staphylococcus aureus-positive sputum: identification of risk factors.

    PubMed

    Shinoda, Y; Matsuoka, T; Mori, T; Yoshida, S; Ohashi, K; Yoshimura, T; Sugiyama, T

    2016-02-01

    Inappropriate antimicrobial treatment could adversely affect the recovery of patients with aspiration pneumonia. We attempted to identify inappropriate antibacterial treatment and to determine the standard use of anti-methicillin-resistant Staphylococcus aureus (MRSA) drugs in aspiration pneumonia patients with MRSA-positive in sputum. Aspiration pneumonia patients with MRSA-positive sputum treated between January 2013 and May 2013 were included in this study to determine the risk factors for death during hospitalization. The relationship between anti-MRSA medicine use and death during hospitalization was also investigated. More than 10⁷ MRSA colony-forming units in sputum culture, creatinine clearance of less than 30 mL/min, and quinolone use were found to be risk factors for death during hospitalization. The death rate during hospitalization was significantly lower in cases a Geckler classification of 4 or 5 when anti-MRSA treatment was initiated soon after the culture was obtained. Therefore, we concluded that the use of quinolones as antibacterial treatment in aspiration pneumonia patients with MRSA-positive sputum should be avoided and that anti-MRSA treatment should be started in cases with good quality sputum cultures. PMID:27004376

  7. The Synthesis of Quinolone Natural Products from Pseudonocardia sp.

    PubMed Central

    Salvaggio, Flavia; Hodgkinson, James T.; Carro, Laura; Geddis, Stephen M.; Galloway, Warren R. J. D.; Welch, Martin

    2015-01-01

    Abstract The synthesis of four quinolone natural products from the actinomycete Pseudonocardia sp. is reported. The key step involved a sp2–sp3 Suzuki–Miyaura reaction between a common boronic ester lateral chain and various functionalised quinolone cores. The quinolones slowed growth of E. coli and S. aureus by inducing extended lag phases.

  8. Modeling the Overproduction of Ribosomes when Antibacterial Drugs Act on Cells.

    PubMed

    Maitra, Arijit; Dill, Ken A

    2016-02-01

    Bacteria that are subjected to ribosome-inhibiting antibiotic drugs show an interesting behavior: Although the drug slows down cell growth, it also paradoxically increases the cell's concentration of ribosomes. We combine our earlier nonlinear model of the energy-biomass balance in undrugged Escherichia coli cells with Michaelis-Menten binding of drugs that inactivate ribosomes. Predictions are in good agreement with experiments on ribosomal concentrations and synthesis rates versus drug concentrations and growth rates. The model indicates that the added drug drives the cell to overproduce ribosomes, keeping roughly constant the level of ribosomes producing ribosomal proteins, an important quantity for cell growth. The model also predicts that ribosomal production rates should increase and then decrease with added drug. This model gives insights into the driving forces in cells and suggests new experiments. PMID:26840738

  9. Improved drug loading and antibacterial activity of minocycline-loaded PLGA nanoparticles prepared by solid/oil/water ion pairing method

    PubMed Central

    Kashi, Tahereh Sadat Jafarzadeh; Eskandarion, Solmaz; Esfandyari-Manesh, Mehdi; Marashi, Seyyed Mahmoud Amin; Samadi, Nasrin; Fatemi, Seyyed Mostafa; Atyabi, Fatemeh; Eshraghi, Saeed; Dinarvand, Rassoul

    2012-01-01

    Background Low drug entrapment efficiency of hydrophilic drugs into poly(lactic-co-glycolic acid) (PLGA) nanoparticles is a major drawback. The objective of this work was to investigate different methods of producing PLGA nanoparticles containing minocycline, a drug suitable for periodontal infections. Methods Different methods, such as single and double solvent evaporation emulsion, ion pairing, and nanoprecipitation were used to prepare both PLGA and PEGylated PLGA nanoparticles. The resulting nanoparticles were analyzed for their morphology, particle size and size distribution, drug loading and entrapment efficiency, thermal properties, and antibacterial activity. Results The nanoparticles prepared in this study were spherical, with an average particle size of 85–424 nm. The entrapment efficiency of the nanoparticles prepared using different methods was as follows: solid/oil/water ion pairing (29.9%) > oil/oil (5.5%) > water/oil/water (4.7%) > modified oil/water (4.1%) > nano precipitation (0.8%). Addition of dextran sulfate as an ion pairing agent, acting as an ionic spacer between PEGylated PLGA and minocycline, decreased the water solubility of minocycline, hence increasing the drug entrapment efficiency. Entrapment efficiency was also increased when low molecular weight PLGA and high molecular weight dextran sulfate was used. Drug release studies performed in phosphate buffer at pH 7.4 indicated slow release of minocycline from 3 days to several weeks. On antibacterial analysis, the minimum inhibitory concentration and minimum bactericidal concentration of nanoparticles was at least two times lower than that of the free drug. Conclusion Novel minocycline-PEGylated PLGA nanoparticles prepared by the ion pairing method had the best drug loading and entrapment efficiency compared with other prepared nanoparticles. They also showed higher in vitro antibacterial activity than the free drug. PMID:22275837

  10. Generation and characterization of quinolone-specific DNA aptamers suitable for water monitoring.

    PubMed

    Reinemann, C; Freiin von Fritsch, U; Rudolph, S; Strehlitz, B

    2016-03-15

    Quinolones are antibiotics that are accredited in human and veterinary medicine but are regularly used in high quantities also in industrial livestock farming. Since these compounds are often only incompletely metabolized, significant amounts contaminate the aquatic environment and negatively impact on a variety of different ecosystems. Although there is increasing awareness of problems caused by pharmaceutical pollution, available methods for the detection and elimination of numerous pharmaceutical residues are currently inefficient or expensive. While this also applies to antibiotics that may lead to multi-drug resistance in pathogenic bacteria, aptamer-based technologies potentially offer alternative approaches for sensitive and efficient monitoring of pharmaceutical micropollutants. Using the Capture-SELEX procedure, we here describe the selection of an aptamer pool with enhanced binding qualities for fluoroquinolones, a widely used group of antibiotics in both human and veterinary medicine. The selected aptamers were shown to detect various quinolones with high specificity, while specific binding activities to structurally unrelated drugs were not detectable. The quinolone-specific aptamers bound to ofloxacin, one of the most frequently prescribed fluoroquinolone, with high affinity (KD=0.1-56.9 nM). The functionality of quinolone-specific aptamers in real water samples was demonstrated in local tap water and in effluents of sewage plants. Together, our data suggest that these aptamers may be applicable as molecular receptors in biosensors or as catcher molecules in filter systems for improved monitoring and treatment of polluted water. PMID:26547431

  11. Conversion of the Pseudomonas aeruginosa Quinolone Signal and Related Alkylhydroxyquinolines by Rhodococcus sp. Strain BG43

    PubMed Central

    Müller, Christine; Birmes, Franziska S.; Niewerth, Heiko

    2014-01-01

    A bacterial strain, which based on the sequences of its 16S rRNA, gyrB, catA, and qsdA genes, was identified as a Rhodococcus sp. closely related to Rhodococcus erythropolis, was isolated from soil by enrichment on the Pseudomonas quinolone signal [PQS; 2-heptyl-3-hydroxy-4(1H)-quinolone], a quorum sensing signal employed by the opportunistic pathogen Pseudomonas aeruginosa. The isolate, termed Rhodococcus sp. strain BG43, cometabolically degraded PQS and its biosynthetic precursor 2-heptyl-4(1H)-quinolone (HHQ) to anthranilic acid. HHQ degradation was accompanied by transient formation of PQS, and HHQ hydroxylation by cell extracts required NADH, indicating that strain BG43 has a HHQ monooxygenase isofunctional to the biosynthetic enzyme PqsH of P. aeruginosa. The enzymes catalyzing HHQ hydroxylation and PQS degradation were inducible by PQS, suggesting a specific pathway. Remarkably, Rhodococcus sp. BG43 is also capable of transforming 2-heptyl-4-hydroxyquinoline-N-oxide to PQS. It thus converts an antibacterial secondary metabolite of P. aeruginosa to a quorum sensing signal molecule. PMID:25239889

  12. Rhodomyrtone: a new candidate as natural antibacterial drug from Rhodomyrtus tomentosa.

    PubMed

    Limsuwan, Surasak; Trip, Erik N; Kouwen, Thijs R H M; Piersma, Sjouke; Hiranrat, Asadhawut; Mahabusarakam, Wilawan; Voravuthikunchai, Supayang P; van Dijl, Jan Maarten; Kayser, Oliver

    2009-06-01

    Rhodomyrtone [6,8-dihydroxy-2,2,4,4-tetramethyl-7-(3-methyl-1-oxobutyl)-9-(2-methylpropyl)-4,9-dihydro-1H-xanthene-1,3(2H)-di-one] from Rhodomyrtus tomentosa (Aiton) Hassk. displayed significant antibacterial activities against gram-positive bacteria including Bacillus cereus, Bacillus subtilis, Enterococcus faecalis, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Staphylococcus epidermidis, Streptococcus gordonii, Streptococcus mutans, Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus salivarius. Especially noteworthy was the activity against MRSA with a minimum inhibitory concentration (MIC) and a minimum bactericidal concentration (MBC) ranging from 0.39 to 0.78 microg/ml. As shown for S. pyogenes, no surviving cells were detected within 5 and 6h after treatment with the compound at 8MBC and 4MBC concentrations, respectively. Rhodomyrtone displays no bacteriolytic activity, as determined by measurement of the optical density at 620 nm. A rhodomyrtone killing test with S. mutans using phase contrast microscopy showed that this compound caused a few morphological changes as the treated cells were slightly changed in color and bigger than the control when they were killed. Taken together, the results support the view that rhodomyrtone has a strong bactericidal activity on gram-positive bacteria, including major pathogens. PMID:19303274

  13. Drug resistance in community-acquired respiratory tract infections: role for an emerging antibacterial

    PubMed Central

    Aguilar, Lorenzo; Giménez, María-José; Barberán, José

    2010-01-01

    The nasopharynx is the ecological niche where evolution towards resistance occurs in respiratory tract isolates. Dynamics of different bacterial populations in antibiotic-free multibacterial niches are the baseline that antibiotic treatments can alter by shifting the competitive balance in favor of resistant populations. For this reason, antibiotic resistance is increasingly being considered to be an ecological problem. Traditionally, resistance has implied the need for development of new antibiotics for which basic efficacy and safety data are required prior to licensing. Antibiotic development is mainly focused on demonstrating clinical efficacy and setting susceptibility breakpoints for efficacy prediction. However, additional information on pharmacodynamic data predicting absence of selection of resistance and of resistant subpopulations, and specific surveillance on resistance to core antibiotics (to detect emerging resistances and its link with antibiotic consumption in the community) are valuable data in defining the role of a new antibiotic, not only from the perspective of its therapeutic potential but also from the ecologic perspective (countering resistances to core antibiotics in the community). The documented information on cefditoren gleaned from published studies in recent years is an example of the role for an emerging oral antibacterial facing current antibiotic resistance in community-acquired respiratory tract infections. PMID:21694892

  14. Nitroimidazoles, Quinolones and Oxazolidinones as Fluorine Bearing Antitubercular Clinical Candidates.

    PubMed

    Patel, Rahul V; Keum, Young-Soo; Park, Se Won

    2015-01-01

    Tuberculosis is a leading killer of lives worldwide and the global curse of multi-drug resistant tuberculosis is attaining really dangerous levels. Synergistic interaction of HIV and TB is the twin epidemics in resource-limited countries as each potentiate progression of the other. The increasing emergence of MDR-TB and XDR-TB place an immense burden for the treatment of TB with currently available drugs. The situation urgently demands for the discovery of new drugs with novel mode of action and differs in structural features in order to overcome resistance appears in conventional TB therapeutics. The present report covers the discovery of three classes of antituberculosis drugs, Nitroimidazoles, Quinolones and Oxazolidinones, undergoing clinical development with fluorine atom in their structures. Highly electronegative fluorine atom plays a signature role in advancing medicinal innovations as it existence in the drug compounds critically influences metabolic stability and lipophilicity thereby delaying its elimination by the body which results into a long term in vivo efficiency of the drug. Presence of fluorine atom(s) in the drug structures described in this report, has been associated with the several fold increase in the overall potency of the compound as demonstrated since the early discoveries. 6 Fluorinated derivatives from these three classes as pretomanid, delamanid, moxifloxacin, gatifloxacin, linezolid and sutezolid have been discussed with their antituberculosis effects, mode of action, chemical synthetic routes and results of clinical studies. PMID:26156417

  15. Synthesis of novel selenium-containing sulfa drugs and their antibacterial activities.

    PubMed

    Abdel-Hafez, Sh H

    2010-01-01

    Synthesis of 3-[4-(N-substituted sulfamoyl)phenyl]-3,4-dihydro-4-oxo-7,9-dimethylpyrido[3',2':4,5]selenolo[3,2-d]pyrimidines, 7-[4-(N-substituted sulfamoyl)phenyl]-7,8-dihydro-8-oxo-3,4-diphenylpyrimido[4',5':4,5]selenolo [2,3-c]pyridazines and 1-[4-(N-substituted sulfamoyl)phenyl]-1,11-dihydro-11-oxo-4-methylpyrimido[4',5':4,5]selenolo[2,3-b]quinolines is reported. 4-Amino-N-pyrimidine-2-ylbenzene sulfonamide (a), 4-amino-N-(2,6-dimetnylpyrimidin-4-yl)benzene sulfonamide (b), N-[(4-aminophenyl)sulfonyl] acetamide (c) with N-ethoxymethyleneamino of selenolo pyridine, selenolo pyridazine and selenolo quinoline derivatives respectively were obtained starting from 1-amino-N-substituted sulfanilamides. Spectroscopic data (IR, (1)H NMR, (13)C NMR and Mass spectral) confirmed the structure of the newly synthesized compounds. Substituted pyrimidines, pyridazines and quinolines were screened for antibacterial activity against gram-positive and gram-negative bacteria. Selenolo derivative of N-[(4-aminophenyl)sulfonyl] acetamide (substitutent of sulfacetamide c) showed strong bactericidal effect against all the tested organisms. Selenolo[3,2-d]pyrimidin (substitutent a) showed a good bactericidal effect against Serratia marcescens, Staphylococcus aureus and Escherichia coli. Compounds Selenolo[2,3-c]pyridazine (substitutent b), Selenolo[2,3-b]quinoline(substitutents c)) exhibited a moderate bactericidal effect against Serratia marcescens. None of the synthesized selenopyridazines has a considerable antimicrobial activity against the tested organisms. The minimum inhibitory concentration (MIC) of the most active compound - 3-[4-(N-acetyl sulfamoyl)phenyl]-3,4-dihydro-4-oxo-7,9-dimethylpyrido[3',2':4,5]selenolo [3,2-d]pyrimidine was 10 mg mL(-1). PMID:20644596

  16. Neisseria gonorrhoeae isolated from disseminated and localised infections in pre-penicillin era. Auxotypes and antibacterial drug resistances.

    PubMed Central

    Catlin, B W; Reyn, A

    1982-01-01

    Interest in the evolution of gonococcal auxotrophy led to a study of 72 strains isolated between 1935 and 1948 from the urogenital tract (57 patients), the eye (two patients), and from disseminated gonococcal infections (11 patients and probably two others). Two cervical isolates with nutritional requirements for proline, arginine, histidine, and biotin were oxidase-positive, Gram-negative diplococci, but their identity as Neisseria gonorrhoeae was uncertain because they were atypically susceptible to colistin and did not produce acid in glucose media. The N gonorrhoeae strains were highly susceptible to 11 other antibacterial drugs but not to sulphadiazine. Defects of one or more pathways for the biosynthesis of methionine, proline, arginine, threonine, lysine, the branched-chain amino acids, hypoxanthine, and thiamine pyrophosphate were found in 39 of the 70 strains, including four isolated in the presulphanilamide era. Unexpectedly, methionine was required for the growth of 11 (21%) of the 52 Danish strains and for 13 (72%) of 18 strains isolated in the USA. The Danish strains included 28 (54%) that did not require any of the compounds used for differentiating auxotypes, whereas this type was represented by only three (17%) of the USA strains. None of the gonococci required uracil or other pyrimidines. This suggests that the requirements for arginine, hypoxanthine, and uracil commonly found in recent isolates from disseminated gonococcal infections probably evolved treatment with sulphonamide was replaced by penicillin. PMID:6805848

  17. In vitro and in vivo efficacy, toxicity, bio-distribution and resistance selection of a novel antibacterial drug candidate

    PubMed Central

    Brunetti, Jlenia; Falciani, Chiara; Roscia, Giulia; Pollini, Simona; Bindi, Stefano; Scali, Silvia; Arrieta, Unai Cossio; Gómez-Vallejo, Vanessa; Quercini, Leila; Ibba, Elisa; Prato, Marco; Rossolini, Gian Maria; Llop, Jordi; Bracci, Luisa; Pini, Alessandro

    2016-01-01

    A synthetic antimicrobial peptide was identified as a possible candidate for the development of a new antibacterial drug. The peptide, SET-M33L, showed a MIC90 below 1.5 μM and 3 μM for Pseudomonas aeruginosa and Klebsiella pneumoniae, respectively. In in vivo models of P. aeruginosa infections, the peptide and its pegylated form (SET-M33L-PEG) enabled a survival percentage of 60–80% in sepsis and lung infections when injected twice i.v. at 5 mg/Kg, and completely healed skin infections when administered topically. Plasma clearance showed different kinetics for SET-M33L and SET-M33L-PEG, the latter having greater persistence two hours after injection. Bio-distribution in organs did not show significant differences in uptake of the two peptides. Unlike colistin, SET-M33L did not select resistant mutants in bacterial cultures and also proved non genotoxic and to have much lower in vivo toxicity than antimicrobial peptides already used in clinical practice. The characterizations reported here are part of a preclinical development plan that should bring the molecule to clinical trial in the next few years. PMID:27169671

  18. In vitro and in vivo efficacy, toxicity, bio-distribution and resistance selection of a novel antibacterial drug candidate.

    PubMed

    Brunetti, Jlenia; Falciani, Chiara; Roscia, Giulia; Pollini, Simona; Bindi, Stefano; Scali, Silvia; Arrieta, Unai Cossio; Gómez-Vallejo, Vanessa; Quercini, Leila; Ibba, Elisa; Prato, Marco; Rossolini, Gian Maria; Llop, Jordi; Bracci, Luisa; Pini, Alessandro

    2016-01-01

    A synthetic antimicrobial peptide was identified as a possible candidate for the development of a new antibacterial drug. The peptide, SET-M33L, showed a MIC90 below 1.5 μM and 3 μM for Pseudomonas aeruginosa and Klebsiella pneumoniae, respectively. In in vivo models of P. aeruginosa infections, the peptide and its pegylated form (SET-M33L-PEG) enabled a survival percentage of 60-80% in sepsis and lung infections when injected twice i.v. at 5 mg/Kg, and completely healed skin infections when administered topically. Plasma clearance showed different kinetics for SET-M33L and SET-M33L-PEG, the latter having greater persistence two hours after injection. Bio-distribution in organs did not show significant differences in uptake of the two peptides. Unlike colistin, SET-M33L did not select resistant mutants in bacterial cultures and also proved non genotoxic and to have much lower in vivo toxicity than antimicrobial peptides already used in clinical practice. The characterizations reported here are part of a preclinical development plan that should bring the molecule to clinical trial in the next few years. PMID:27169671

  19. Norfloxacin, a fluoroquinolone antibacterial agent. Classification, mechanism of action, and in vitro activity.

    PubMed

    Goldstein, E J

    1987-06-26

    Norfloxacin is an orally absorbed fluoroquinolone antibacterial with a fluorine at position 6 and a piperazine ring at position 7. These changes have resulted in a marked enhancement (compared with that of the older quinolones) of in vitro antibacterial activity. Specifically, the antibacterial spectrum of norfloxacin includes Pseudomonas aeruginosa, as well as enteric pathogens. Norfloxacin is also active against both penicillin-susceptible and penicillin-resistant strains of Neisseria gonorrhoeae. Relative to its activity against gram-negative bacteria, norfloxacin is somewhat less active against gram-positive cocci. In general, the staphylococci are more susceptible to the drug than are the streptococci. As with all fluoroquinolones, norfloxacin's activity against anaerobic bacteria is poor. For urinary tract bacterial isolates, the following Bauer-Kirby disk diffusion zone-size breakpoints have been proposed: greater than or equal to 17 mm, susceptible; 13 to 16 mm, intermediate; less than or equal to 12 mm, resistant. Bacteria with minimal inhibitory concentrations (MICs) less than or equal to 16 micrograms/ml are considered susceptible; those with MICs greater than or equal to 32 micrograms/ml are considered resistant to norfloxacin. The mechanism of action of norfloxacin involves inhibition of the A subunit of the important bacterial enzyme DNA gyrase, which is essential for DNA replication. Plasmid-mediated resistance to the fluoroquinolones is not encountered. Further, although some cross-resistance within the fluoroquinolone class has occurred, there is little cross-resistance between norfloxacin and antibiotics of other classes. PMID:3111257

  20. Enhanced efficacy and broadening of antibacterial action of drugs via the use of capped mesoporous nanoparticles.

    PubMed

    Mas, Núria; Galiana, Irene; Mondragón, Laura; Aznar, Elena; Climent, Estela; Cabedo, Nuria; Sancenón, Félix; Murguía, José Ramón; Martínez-Máñez, Ramón; Marcos, María D; Amorós, Pedro

    2013-08-19

    Bug busters: A novel nanodevice consisting of mesoporous nanoparticles loaded with vancomycin and capped with ε-poly-L-lysine (ε-PL) was prepared and its interaction with different Gram-negative bacteria studied. A remarkable improvement in the efficacy of the antimicrobial drug ε-PL and a broadening of the antimicrobial spectrum of vancomycin is demonstrated. PMID:23839913

  1. Thermosensitive hydrogel for periodontal application: in vitro drug release, antibacterial activity and toxicity evaluation.

    PubMed

    Pakzad, Yousef; Ganji, Fariba

    2016-02-01

    Injectable thermosensitive chitosan hydrogel is an attractive temperature-induced sol-gel solution that is widely used in drug delivery and biomedical applications. In this study, an injectable antimicrobial delivery system for periodontal treatment based on chitosan/gelatin/β-glycerolphosphate solution has been developed. The result of thermal and mechanical evaluations of chitosan/gelatin/β-glycerolphosphate hydrogel showed that adding gelatin to chitosan/β-glycerolphosphate solution significantly decreased gelling time and increased gel strength at 37℃. The antimicrobial agents chosen for release studies were metronidazole with a low molecular weight and vancomycin hydrochloride with a high molecular weight. The initial burst and total in vitro drug release for metronidazole was 13% and 67%, respectively. The initial burst and total drug release for vancomycin hydrochloride was relatively low at 3% and 23%, respectively. The momentary and total percentage of metronidazole accumulated in the phosphate buffer revealed that chitosan/gelatin/β-glycerolphosphate can develop and maintain sustained release of metronidazole in concentrations that are effective for eliminating pathogenic bacteria over time. Cytotoxicity evaluations show that chitosan/gelatin/β-glycerolphosphate thermosensitive hydrogel is a drug carrier with no cytotoxic effects. PMID:26686586

  2. Phytochemicals increase the antibacterial activity of antibiotics by acting on a drug efflux pump

    PubMed Central

    Ohene-Agyei, Thelma; Mowla, Rumana; Rahman, Taufiq; Venter, Henrietta

    2014-01-01

    Drug efflux pumps confer resistance upon bacteria to a wide range of antibiotics from various classes. The expression of efflux pumps are also implicated in virulence and biofilm formation. Moreover, organisms can only acquire resistance in the presence of active drug efflux pumps. Therefore, efflux pump inhibitors (EPIs) are attractive compounds to reverse multidrug resistance and to prevent the development of resistance in clinically relevant bacterial pathogens. We investigated the potential of pure compounds isolated from plants to act as EPIs. In silico screening was used to predict the bioactivity of plant compounds and to compare that with the known EPI, phe-arg-β-naphthylamide (PAβN). Subsequently, promising products have been tested for their ability to inhibit efflux. Plumbagin nordihydroguaretic acid (NDGA) and to a lesser degree shikonin, acted as sensitizers of drug-resistant bacteria to currently used antibiotics and were able to inhibit the efflux pump-mediated removal of substrate from cells. We demonstrated the feasibility of in silico screening to identify compounds that potentiate the action of antibiotics against drug-resistant strains and which might be potentially useful lead compounds for an EPI discovery program. PMID:25224951

  3. Biosurfactins production by Bacillus amyloliquefaciens R3 and their antibacterial activity against multi-drug resistant pathogenic E. coli.

    PubMed

    Chi, Zhe; Rong, Yan-Jun; Li, Yang; Tang, Mei-Juan; Chi, Zhen-Ming

    2015-05-01

    In this work, the anti-Escherichia coli activity of the bioactive substances produced by Bacillus amyloliquefaciens R3 was examined. A new and cheap medium for production of the anti-E. coli substances which contained 20.0 g L(-1) soybean powder, 20.0 g L(-1) wheat flour, pH 6.0 was developed. A crude surfactant concentration of 0.48 mg mL(-1) was obtained after 27 h of 10-L fermentation, and the diameter of the clear zone on the plate seeded with the pathogenic E. coli 2# was 23.3 mm. A preliminary characterization suggested that the anti-E. coli substances produced by B. amyloliquefaciens R3 were the biosurfactins (F1, F2, F3, F4, and F5) with amino acids (GLLVDLL) and hydroxy fatty acids (of 12-15 carbons in length). It was found that all the strains of the pathogenic E. coli showed resistance to several different antibiotics, suggesting that they were the multi-drug resistance and all the strains of the pathogenic E. coli were sensitive to the biosurfactins, indicating that the biosurfactins produced by B. amyloliquefaciens R3 had a broad spectrum of antibacterial activity against the pathogenic E. coli with multi-drug resistant profiles. After the treatment with the purified biosurfactin (F1), the cell membrane of both the whole cells and protoplasts of the E. coli 2# was damaged and the whole cells of the bacterium were broken. PMID:25407729

  4. Simulating Serial-Target Antibacterial Drug Synergies Using Flux Balance Analysis.

    PubMed

    Krueger, Andrew S; Munck, Christian; Dantas, Gautam; Church, George M; Galagan, James; Lehr, Joseph; Sommer, Morten O A

    2016-01-01

    Flux balance analysis (FBA) is an increasingly useful approach for modeling the behavior of metabolic systems. However, standard FBA modeling of genetic knockouts cannot predict drug combination synergies observed between serial metabolic targets, even though such synergies give rise to some of the most widely used antibiotic treatments. Here we extend FBA modeling to simulate responses to chemical inhibitors at varying concentrations, by diverting enzymatic flux to a waste reaction. This flux diversion yields very similar qualitative predictions to prior methods for single target activity. However, we find very different predictions for combinations, where flux diversion, which mimics the kinetics of competitive metabolic inhibitors, can explain serial target synergies between metabolic enzyme inhibitors that we confirmed in Escherichia coli cultures. FBA flux diversion opens the possibility for more accurate genome-scale predictions of drug synergies, which can be used to suggest treatments for infections and other diseases. PMID:26821252

  5. Simulating Serial-Target Antibacterial Drug Synergies Using Flux Balance Analysis

    PubMed Central

    Dantas, Gautam; Church, George M.; Galagan, James; Lehár, Joseph; Sommer, Morten O. A.

    2016-01-01

    Flux balance analysis (FBA) is an increasingly useful approach for modeling the behavior of metabolic systems. However, standard FBA modeling of genetic knockouts cannot predict drug combination synergies observed between serial metabolic targets, even though such synergies give rise to some of the most widely used antibiotic treatments. Here we extend FBA modeling to simulate responses to chemical inhibitors at varying concentrations, by diverting enzymatic flux to a waste reaction. This flux diversion yields very similar qualitative predictions to prior methods for single target activity. However, we find very different predictions for combinations, where flux diversion, which mimics the kinetics of competitive metabolic inhibitors, can explain serial target synergies between metabolic enzyme inhibitors that we confirmed in Escherichia coli cultures. FBA flux diversion opens the possibility for more accurate genome-scale predictions of drug synergies, which can be used to suggest treatments for infections and other diseases. PMID:26821252

  6. Cecal Enlargement and Microbial Flora in Suckling Mice Given Antibacterial Drugs

    PubMed Central

    Savage, Dwayne C.; McAllister, Julia Sue

    1971-01-01

    Enlargement and microbial colonization of the cecum were examined in neonatal mice suckling mothers drinking either water or an aqueous solution of penicillin. The full ceca increased in weight at the same rate in both drug-treated and control mice during the first 15 to 17 days after birth. Thereafter, cecal weight increased at a greater rate in the drug-treated animals than in the untreated controls. At weaning, the ceca in treated mice were two to three times the size of control organs and remained enlarged as long as penicillin was given. The enlarged ceca did not differ histologically from those in controls. From birth, the cecal microflora in the drug-treated mice differed qualitatively and quantitatively and in colonization pattern from the flora of control mice. The ceca of untreated animals were colonized primarily by large populations of lactobacilli during the first week after birth, small populations of coliforms and enterococci during the second week, and enormous populations of bacteroides and certain gram-negative fusiform-shaped anaerobic bacteria during the third week. In contrast, the organs of the treated mice were populated by large populations of coliforms and enterococci during the first week and enormous populations of clostridia and unusual gram-negative nonsporeforming bacteria during the third week. These large abnormal populations were present in the ceca as they enlarged during the third week after birth in the drug-treated animals. These findings confirm that only certain populations of anaerobic bacteria can act to maintain cecal size in normal animals. Images PMID:16557975

  7. Virulence factors in urinary Escherichia coli strains: phylogenetic background and quinolone and fluoroquinolone resistance.

    PubMed

    Piatti, Gabriella; Mannini, Alessandro; Balistreri, Maria; Schito, Anna Maria

    2008-02-01

    Quinolone- and fluoroquinolone-resistant Escherichia coli strains harbor fewer virulence factors than susceptible strains. The reasons underlying this correlation are incompletely understood. We investigated the phylogenetic background, the presence of the papC, hlyA, and cnf1 (pathogenicity island II(J96)-associated), fimA, iss, and iutA genes, and the presence of type 1 fimbriae, P fimbriae, and hemolysin in 243 urinary E. coli isolates resistant only to quinolones (8%), resistant to both quinolones and fluoroquinolones (51%), or susceptible to both drugs (41%). Group B2 accounted for 56% of the isolates, showing a significantly higher prevalence among fluoroquinolone-susceptible strains than among resistant strains (65% versus 50% [P = 0.03]). hly and cnf1 were significantly more associated with susceptibility (P < 0.001) and with group B2 (P < 0.001 for group B2 versus groups A and D). However, within group B2, fluoroquinolone-resistant strains showed lower prevalences of papC, hlyA, and cnf1 than their susceptible counterparts (P < 0.001). In contrast, the incidence of iutA appeared higher for refractory isolates, including group B2, than for susceptible isolates (P < 0.001). Only in group B2 did fluoroquinolone-resistant strains reveal a lesser ability to agglutinate Saccharomyces cerevisiae (7%) than quinolone-resistant (87%) and susceptible (80%) isolates, despite uniform possession of fimA genes. No similar contrast emerged for expression of hemolysin and P fimbriae. Mutations conferring quinolone and fluoroquinolone resistance may thus require a particular genetic background, not strictly correlated with phylogenetic groups. More interestingly, the mutational event itself can affect the expression of type 1 fimbriae, at least in the prevalent and complex B2 strains. PMID:18057134

  8. [Susceptibility of ESBL-producing Escherichia coli and Klebsiella pneumoniae to various antibacterial agents].

    PubMed

    Nakamura, Tatsuya; Komatsu, Masaru

    2005-02-01

    With the increasing use of broad-spectrum antibacterial agents, the increase in various drug-resistant bacterial strains has become a concern in recent years. Especially, the development of drug-resistance by Enterobacteriaceae which significantly affects therapy and prognosis in sepsis and lower gastrointestinal post-operative infection. The extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae strains isolated in the Surveillance Program of Bacterial Resistance in Kinki region of Japan (SBRK) were supplied between November 2000 and March 2003. The susceptibilities of them to 16 kinds of antimicrobial agents were investigated. The number of them was 48 strains consisting of 36 Escherichia coli strains (75%) and 12 Klebsiella pneumoniae strains (25%). Our focus was on carbapenem and the new quinolone antibacterial agents. Among the 16 major antibacterial agents examined, carbapenem had low MIC50/90 values. Meropenem had a MIC50/90 of 0.03/0.06microg/ml, followed by biapenem (0.12/0.5), imipenem (0.25/0.5) and panipenem (0.25/0.5). Among cephem, ceftazidime had the lowest MIC50 at 4 microg/ml. All four of the cephem agents had a MIC90 of greater than 128microg/ml. Among beta-lactamase inhibitors, tazobactam/piperacillin had the lowest MIC50 at 4 microg/ml, and sulbactam/cefoperazone had a MIC50 of 32 microg/ml. Among the new quinolones, prulifloxacin had the lowest MIC50 at 1 microg/ml, and the other drugs had a MIC50 of 2 microg/ml. The resistance rate of ciprofloxacin was 61.1% in E. coli and 16.6% in K. pneumoniae. Comparison of drug-sensitivity to cephem by ESBL-gene type revealed that cefpirome, cefepime and cefozopran had higher MIC50/90 values against the CTX-M group with a MIC50 of greater than 128microg/ml. Ceftazidime and aztreonam had higher MIC50/90 values against the TEM/SHV group than those against the CTX-M group. In the CTX-M group, the MIC50 was 4 and 16microg/ml, respectively. PMID:15847220

  9. Genetic detection of quinolone resistance in Haemophilus parainfluenzae: Mutations in the quinolone resistance-determining regions of gyrA and parC.

    PubMed

    Law, Dennis Ks; Shuel, Michelle; Bekal, Sadjia; Bryce, Elizabeth; Tsang, Raymond Sw

    2010-01-01

    The quinolone resistance-determining regions of gyrA and parC of both quinolone-sensitive and quinolone-resistant Haemophilus parainfluenzae strains were amplified and sequenced. Similar to Haemophilus influenzae, resistance to quinolones in H parainfluenzae is associated with mutations in the quinolone resistance-determining regions of both gyrA and parC. The present study discusses the importance of this finding. PMID:21358875

  10. Study on the interaction between antibacterial drug and bovine serum albumin: A spectroscopic approach

    NASA Astrophysics Data System (ADS)

    Naik, P. N.; Chimatadar, S. A.; Nandibewoor, S. T.

    2009-09-01

    The binding of sulfamethoxazole (SMZ) to bovine serum albumin (BSA) was investigated by spectroscopic methods viz., fluorescence, FT-IR and UV-vis absorption techniques. The binding parameters have been evaluated by fluorescence quenching method. The thermodynamic parameters, Δ H°, Δ S°and Δ G° were observed to be -58.0 kJ mol -1, -111 J K -1 mol -1 and -24 kJ mol -1, respectively. These indicated that the hydrogen bonding and weak van der Waals forces played a major role in the interaction. Based on the Forster's theory of non-radiation energy transfer, the binding average distance, r, between the donor (BSA) and acceptor (SMZ) was evaluated and found to be 4.12 nm. Spectral results showed the binding of SMZ to BSA induced conformational changes in BSA. The effect of common ions and some of the polymers used in drug delivery for control release was also tested on the binding of SMZ to BSA. The effect of common ions revealed that there is adverse effect on the binding of SMZ to BSA.

  11. Antibacterial activity of nineteen selected natural products against multi-drug resistant Gram-negative phenotypes.

    PubMed

    Mbaveng, Armelle T; Sandjo, Louis P; Tankeo, Simplice B; Ndifor, Ache R; Pantaleon, Ambassa; Nagdjui, Bonaventure T; Kuete, Victor

    2015-01-01

    The present study was designed to assess the antimicrobial activity of 19 natural products belonging to terpenoids, alkaloids, thiophenes and phenolics against a panel of 14 Gram-negative multidrug-resistant (MDR) bacteria. The results demonstrated that amongst the studied compounds, alkaloids and terpenoids were less active contrary to flavonoids: neocyclomorusin (3) and candidone (6) and isoflavonoids: neobavaisoflavone (8) and daidzein (12). Thiophene, 2-(penta-1,3-diynyl)-5-(3,4-dihydroxybut-1-ynyl)thiophene (17) showed moderate and selective activities. Compounds 3, 6, 8 and 12 displayed minimal inhibitory concentration (MIC) ranged from 4 to 256 μg/mL on all the 14 tested bacteria. MIC values below 10 μg/mL were obtained with 8, 3, 6 and 12 against 50, 42.9, 35.7 and 21.4 % of the tested bacteria. The lowest MIC value of 4 μg/mL was obtained with compound 3 against Klebsiella pneumoniae ATCC11296, Enterobacter cloacae BM47, compound 6 against Escherichia coli ATCC8739, K. pneumoniae ATCC11296, E. cloacae BM47 and compound 8 against K. pneumoniae ATCC11296 and E. cloacae BM47. The activity of flavonoid 3 was better or equal to that of chloramphenicol in all tested K. pneumoniae, Providencia stuartii, E. aerogenes, E. cloacae and Pseudomonas aeruginosa strains. Within isoflavonoids, neobavaisoflavone scaffold was detected as a pharmacophoric moiety. This study indicates that natural products such as 3, 6 and 8 could be explored more to develop antimicrobial drugs to fight MDR bacterial infections. PMID:26753111

  12. Antibacterial modification of an injectable, biodegradable, non-cytotoxic block copolymer-based physical gel with body temperature-stimulated sol-gel transition and controlled drug release.

    PubMed

    Wang, Xiaowen; Hu, Huawen; Wang, Wenyi; Lee, Ka I; Gao, Chang; He, Liang; Wang, Yuanfeng; Lai, Chuilin; Fei, Bin; Xin, John H

    2016-07-01

    Biomaterials are being extensively used in various biomedical fields; however, they are readily infected with microorganisms, thus posing a serious threat to the public health care. We herein presented a facile route to the antibacterial modification of an important A-B-A type biomaterial using poly (ethylene glycol) methyl ether (mPEG)- poly(ε-caprolactone) (PCL)-mPEG as a typical model. Inexpensive, commercial bis(2-hydroxyethyl) methylammonium chloride (DMA) was adopted as an antibacterial unit. The effective synthesis of the antibacterial copolymer mPEG-PCL-∼∼∼-PCL-mPEG (where ∼∼∼ denotes the segment with DMA units) was well confirmed by FTIR and (1)H NMR spectra. At an appropriate modification extent, the DMA unit could render the copolymer mPEG-PCL-∼∼∼-PCL-mPEG highly antibacterial, but did not largely alter its fascinating intrinsic properties including the thermosensitivity (e.g., the body temperature-induced sol-gel transition), non-cytotoxicity, and controlled drug release. A detailed study on the sol-gel-sol transition behavior of different copolymers showed that an appropriate extent of modification with DMA retained a sol-gel-sol transition, despite the fact that a too high extent caused a loss of sol-gel-sol transition. The hydrophilic and hydrophobic balance between mPEG and PCL was most likely broken upon a high extent of quaternization due to a large disturbance effect of DMA units at a large quantity (as evidenced by the heavily depressed PCL segment crystallinity), and thus the micelle aggregation mechanism for the gel formation could not work anymore, along with the loss of the thermosensitivity. The work presented here is highly expected to be generalized for synthesis of various block copolymers with immunity to microorganisms. Light may also be shed on understanding the phase transition behavior of various multiblock copolymers. PMID:27022875

  13. Detection of quinolone-resistant Neisseria gonorrhoeae.

    PubMed Central

    Kam, K M; Wong, P W; Cheung, M M; Ho, N K

    1996-01-01

    The present National Committee for Clinical Laboratory Standards (NCCLS) guideline for testing Neisseria gonorrhoeae quinolone susceptibility defines only a susceptible category for ciprofloxacin, enoxacin, lomefloxacin, and ofloxacin, while susceptible, intermediate, and resistant categories are defined for fleroxacin. To further define the criteria for detection of quinolone resistance in gonococci, by standard disk diffusion and agar dilution methodologies recommended by the NCCLS, we tested 29 strains of quinolone-resistant N. gonorrhoeae (QRNG) recently isolated from ofloxacin-treated patients who were considered clinical failures. Regression analyses were performed on these results together with those of another 20 strains showing reduced susceptibility and 13 fully susceptible strains (ofloxacin MICs of < or = 0.25 microgram/ml). With 5-micrograms ofloxacin disks, resistance in 27 (93.1%) of the QRNG strains (MICs of > 1 microgram/ml) was detected by the criterion of a zone diameter of < 22 mm, while in the remaining 2 (6.9%), the disks failed to detect resistance. A cluster of 15 highly resistant strains showed ofloxacin MICs of > 4 micrograms/ml and zone diameters of < 13 mm. When tested with 5-micrograms ciprofloxacin disks, the corresponding values for resistance and high-level resistance of these QRNG strains were < 25 mm (MICs of > 0.5 micrograms/ml) and < 15 mm (MICs of > 2 micrograms /ml), respectively. Six strains for which ofloxacin MICs were > or = 8 micrograms/ml showed no zones at all with both 5-micrograms ofloxacin and 5-micrograms ciprofloxacin disks. These QRNG strains are now firmly established in the Southeast Asia region, and it is important for clinical laboratories to recognize these clinically resistant strains and to monitor their spread. PMID:8735098

  14. Quinolone-Hydroxyquinoline Tautomerism in Quinolone 3-Esters. Preserving the 4-Oxoquinoline Structure To Retain Antimalarial Activity.

    PubMed

    Horta, Pedro; Kuş, Nihal; Henriques, Marta Sofia C; Paixão, José A; Coelho, Lis; Nogueira, Fátima; O'Neill, Paul M; Fausto, Rui; Cristiano, Maria Lurdes Santos

    2015-12-18

    Recent publications report in vitro activity of quinolone 3-esters against the bc1 protein complex of Plasmodium falciparum and the parasite. Docking studies performed in silico at the yeast Qo site established a key role for the 4-oxo and N-H groups in drug-target interactions. Thus, the possibility of 4-oxoquinoline/4-hydroxyquinoline tautomerism may impact in pharmacologic profiles and should be investigated. We describe the synthesis, structure, photochemistry, and activity against multidrug-resistant P. falciparum strain Dd2 of ethyl 4-oxo-7-methylquinoline-3-carboxylate (7Me-OQE) and ethyl 4-hydroxy-5-methylquinoline-3-carboxylate (5Me-HQE), obtained from diethyl 2-[((3-methylphenyl)amino)methylene]malonate. Theoretically (B3LYP/6-311++G(d,p)), 5Me-HQE and 7Me-OQE show clear preference for the hydroxyquinoline form. The difference between the lowest energy hydroxyquinoline and quinolone forms is 27 and 38 kJ mol(-1), for 5Me-HQE and 7Me-OQE, respectively. Calculations of aromaticity indexes show that in 5Me-HQE both rings are aromatic, while in the corresponding oxo tautomers the nitrogen-containing ring is essentially non-aromatic. The structure of monomeric 5Me-HQE was studied using matrix isolation coupled to FTIR spectroscopy. No traces of 4-oxoquinoline tautomers were found in the experimental IR spectra, revealing that the species present in the crystal, 5Me-HQE·HCl, was lost HCl upon sublimation but did not tautomerize. Continuous broadband irradiation (λ > 220 nm; 130 min) of the matrix led to only partial photodecomposition of 5Me-HQE (ca. 1/3). PMID:26551438

  15. Fluoroquinolone-gyrase-DNA complexes: two modes of drug binding.

    PubMed

    Mustaev, Arkady; Malik, Muhammad; Zhao, Xilin; Kurepina, Natalia; Luan, Gan; Oppegard, Lisa M; Hiasa, Hiroshi; Marks, Kevin R; Kerns, Robert J; Berger, James M; Drlica, Karl

    2014-05-01

    DNA gyrase and topoisomerase IV control bacterial DNA topology by breaking DNA, passing duplex DNA through the break, and then resealing the break. This process is subject to reversible corruption by fluoroquinolones, antibacterials that form drug-enzyme-DNA complexes in which the DNA is broken. The complexes, called cleaved complexes because of the presence of DNA breaks, have been crystallized and found to have the fluoroquinolone C-7 ring system facing the GyrB/ParE subunits. As expected from x-ray crystallography, a thiol-reactive, C-7-modified chloroacetyl derivative of ciprofloxacin (Cip-AcCl) formed cross-linked cleaved complexes with mutant GyrB-Cys(466) gyrase as evidenced by resistance to reversal by both EDTA and thermal treatments. Surprisingly, cross-linking was also readily seen with complexes formed by mutant GyrA-G81C gyrase, thereby revealing a novel drug-gyrase interaction not observed in crystal structures. The cross-link between fluoroquinolone and GyrA-G81C gyrase correlated with exceptional bacteriostatic activity for Cip-AcCl with a quinolone-resistant GyrA-G81C variant of Escherichia coli and its Mycobacterium smegmatis equivalent (GyrA-G89C). Cip-AcCl-mediated, irreversible inhibition of DNA replication provided further evidence for a GyrA-drug cross-link. Collectively these data establish the existence of interactions between the fluoroquinolone C-7 ring and both GyrA and GyrB. Because the GyrA-Gly(81) and GyrB-Glu(466) residues are far apart (17 Å) in the crystal structure of cleaved complexes, two modes of quinolone binding must exist. The presence of two binding modes raises the possibility that multiple quinolone-enzyme-DNA complexes can form, a discovery that opens new avenues for exploring and exploiting relationships between drug structure and activity with type II DNA topoisomerases. PMID:24497635

  16. 4-Quinolone Alkaloids from Melochia odorata

    PubMed Central

    Jadulco, Raquel C.; Pond, Christopher D.; Van Wagoner, Ryan M.; Koch, Michael; Gideon, Osia G.; Matainaho, Teatulohi K.; Piskaut, Pius; Barrows, Louis R.

    2014-01-01

    The methanol extract of Melochia odorata yielded three 4-quinolone alkaloids including waltherione A (1) and two new alkaloids, waltherione C (2) and waltherione D (3). Waltheriones A and C showed significant activities in an in vitro anti-HIV cytoprotection assay at concentrations of 56.2 and 0.84 μM, and inhibition of HIV P24 formation of more than 50% at 1.7 and 0.95 μM, respectively. The structures of the alkaloids were established by spectroscopic data interpretation. PMID:24392742

  17. Novel 3-Aminothiazolquinolones: Design, Synthesis, Bioactive Evaluation, SARs, and Preliminary Antibacterial Mechanism.

    PubMed

    Cui, Sheng-Feng; Addla, Dinesh; Zhou, Cheng-He

    2016-05-26

    A series of novel 3-aminothiazolquinolones as analogues of quinolone antibacterial agents were designed and synthesized in an effort to circumvent quinolone resistance. Among these 3-aminothiazolquinolones, 3-(2-aminothiazol-4-yl)-7-chloro-6-(pyrrolidin-1-yl) quinolone 12b exhibited potent antibacterial activity, low cytotoxicity to hepatocyte cells, strong inhibitory potency to DNA gyrase, and a broad antimicrobial spectrum including against multidrug-resistant strains. This active molecule 12b also induced bacterial resistance more slowly than norfloxacin. Analysis of structure-activity relationships (SARs) disclosed that the 2-aminothiazole fragment at the 3-position of quinolone plays an important role in exerting antibacterial activity. Molecular modeling and experimental investigation of aminothiazolquinolone 12b with DNA from a sensitive methicillin-resistant Staphylococcus aureus (MRSA) strain revealed that the possible antibacterial mechanism might be related to the formation of a compound 12b-Cu(2+)-DNA ternary complex in which the Cu(2+) ion acts as a bridge between the backbone of 3-aminothiazolquinolone and the phosphate group of the nucleic acid. PMID:27115717

  18. Quinolone resistance in Escherichia coli from Accra, Ghana

    PubMed Central

    2011-01-01

    Background Antimicrobial resistance is under-documented and commensal Escherichia coli can be used as indicator organisms to study the resistance in the community. We sought to determine the prevalence of resistance to broad-spectrum antimicrobials with particular focus on the quinolones, which have recently been introduced in parts of Africa, including Ghana. Results Forty (13.7%) of 293 E. coli isolates evaluated were nalidixic acid-resistant. Thirteen (52%) of 2006 and 2007 isolates and 10 (66.7%) of 2008 isolates were also resistant to ciprofloxacin. All but one of the quinolone-resistant isolates were resistant to three or more other antimicrobial classes. Sequencing the quinolone-resistance determining regions of gyrA and parC, which encode quinolone targets, revealed that 28 quinolone-resistant E. coli harboured a substitution at position 83 of the gyrA gene product and 20 of these isolates had other gyrA and/or parC substitutions. Horizontally-acquired quinolone-resistance genes qnrB1, qnrB2, qnrS1 or qepA were detected in 12 of the isolates. In spite of considerable overall diversity among E. coli from Ghana, as evaluated by multilocus sequence typing, 15 quinolone-resistant E. coli belonged to sequence type complex 10. Five of these isolates carried qnrS1 alleles. Conclusions Quinolone-resistant E. coli are commonly present in the faecal flora of Accra residents. The isolates have evolved resistance through multiple mechanisms and belong to very few lineages, suggesting clonal expansion. Containment strategies to limit the spread of quinolone-resistant E. coli need to be deployed to conserve quinolone effectiveness and promote alternatives to their use. PMID:21352598

  19. DNA interactions and promotion in antibacterial activities of ciprofloxacin drug due to formation of mixed-ligand complexes of oxovanadium(IV).

    PubMed

    Patel, M N; Patel, S H; Chhasatia, M R; Desai, C R

    2010-03-01

    Mixed-ligand complexes of oxovanadium(IV) of the type [VOAL]*2H(2)O [where A = ciprofloxacin and L = uninegative bidentate ligands] have been synthesized and characterized using infrared spectra, electronic spectra, magnetic measurements, elemental analyses, thermal investigation, and mass spectroscopy. Here, we tried to increase an antibacterial activity of ciprofloxacin drug due to formation of mixed-ligand complexes. The complexes were found to be more potent compare to some standard drugs, ligands and metal salt against selective gram(+ve) and gram(-ve) organisms. Binding of the complexes with DNA have been investigated by spectroscopic absorption titration and viscometric techniques. The mixed-ligand complexes show good binding ability. The cleavage efficacy has been determined using gel electrophoresis method and complexes were found to be more active compared to parental ligands and metal salt. PMID:20408051

  20. In-vitro susceptibility of quinolone-resistant clinical isolates of Escherichia coli to fosfomycin trometamol.

    PubMed

    Ungheri, D; Albini, E; Belluco, G

    2002-06-01

    Escherichia coli (E. coli) is the most commonly isolated microorganism in uncomplicated lower urinary tract infections (UTI). Due to the increased isolation of E. coli strains resistant to quinolones, it is important to have available alternative drugs to this class of antibiotics as therapy for UTIs caused by this pathogen. Among the large number of currently available antimicrobial agents, fosfomycin trometamol is a useful alternative due to its peculiar microbiological and pharmacokinetic properties. Therefore, we tested the in vitro susceptibility of 79 quinolone-resistant clinical urinary isolates of E. coli to fosfomycin trometamol in comparison with amoxicillin, chloramphenicol, cotrimoxazole, netilmicin, nitrofurantoin and tetracycline. Fosfomycin trometamol showed high activity with a MIC90 of 4 mg/l. While no strains were resistant to fosfomycin trometamol, 83.5%, 63.3%, 58.2%, and 48.1% of the isolates were resistant to tetracycline, amoxicillin, chloramphenicol and cotrimoxazole, respectively. Nitrofurantoin and netilmicin resistance was present only in 12.7% and 6.3% of the strains, respectively. In conclusion, fosfomycin trometamol has retained its activity against quinolone-resistant strains of E. coli and cross-resistance with other classes of antimicrobial agents is not presently a problem. The strains tested did present high levels of resistance to other classes of antibiotics. PMID:12120876

  1. Dynamics of Quinolone Resistance in Fecal Escherichia coli of Finishing Pigs after Ciprofloxacin Administration

    PubMed Central

    HUANG, Kang; XU, Chang-Wen; ZENG, Bo; XIA, Qing-Qing; ZHANG, An-Yun; LEI, Chang-Wei; GUAN, Zhong-Bin; CHENG, Han; WANG, Hong-Ning

    2014-01-01

    ABSTRACT Escherichia coli resistance to quinolones has now become a serious issue in large-scale pig farms of China. It is necessary to study the dynamics of quinolone resistance in fecal Escherichia coli of pigs after antimicrobial administration. Here, we present the hypothesis that the emergence of resistance in pigs requires drug accumulation for 7 days or more. To test this hypothesis, 26 pigs (90 days old, about 30 kg) not fed any antimicrobial after weaning were selected and divided into 2 equal groups: the experimental (EP) group and control (CP) group. Pigs in the EP group were orally treated daily with 5 mg ciprofloxacin/kg of body weight for 30 days, and pigs in the CP group were fed a normal diet. Fresh feces were collected at 16 time points from day 0 to day 61. At each time point, ten E. coli clones were tested for susceptibility to quinolones and mutations of gyrA and parC. The results showed that the minimal inhibitory concentration (MIC) for ciprofloxacin increased 16-fold compared with the initial MIC (0.5 µg/ml) after ciprofloxacin administration for 3 days and decreased 256-fold compared with the initial MIC (0.5 µg/ml) after ciprofloxacin withdrawal for 26 days. GyrA (S83L, D87N/ D87Y) and parC (S80I) substitutions were observed in all quinolone-resistant E. coli (QREC) clones with an MIC ≥8 µg/ml. This study provides scientific theoretical guidance for the rational use of antimicrobials and the control of bacterial resistance. PMID:24919413

  2. Chemical conjugation of 2-hexadecynoic acid to C5-curcumin enhances its antibacterial activity against multi-drug resistant bacteria.

    PubMed

    Sanabria-Ríos, David J; Rivera-Torres, Yaritza; Rosario, Joshua; Gutierrez, Ricardo; Torres-García, Yeireliz; Montano, Nashbly; Ortíz-Soto, Gabriela; Ríos-Olivares, Eddy; Rodríguez, José W; Carballeira, Néstor M

    2015-11-15

    The first total synthesis of a C5-curcumin-2-hexadecynoic acid (C5-Curc-2-HDA, 6) conjugate was successfully performed. Through a three-step synthetic route, conjugate 6 was obtained in 13% overall yield and tested for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains. Our results revealed that 6 was active against eight MRSA strains at MICs that range between 31.3 and 62.5 μg/mL. It was found that the presence of 2-hexadecynoic acid (2-HDA, 4) in conjugate 6 increased 4-8-fold its antibacterial activity against MRSA strains supporting our hypothesis that the chemical connection of 4 to C5-curcumin (2) increases the antibacterial activity of 2 against Gram-positive bacteria. Combinational index (CIn) values that range between 1.6 and 2.3 were obtained when eight MRSA strains were treated with an equimolar mixture of 2 and 4. These results demonstrated that an antagonistic effect is taking place. Finally, it was investigated whether conjugate 6 can affect the replication process of S. aureus, since this compound inhibited the supercoiling activity of the S. aureus DNA gyrase at minimum inhibitory concentrations (MIC) of 250 μg/mL (IC50=100.2±13.9 μg/mL). Moreover, it was observed that the presence of 4 in conjugate 6 improves the anti-topoisomerase activity of 2 towards S. aureus DNA gyrase, which is in agreement with results obtained from antibacterial susceptibility tests involving MRSA strains. PMID:26483137

  3. Cytotoxic and antibacterial substances against multi-drug resistant pathogens from marine sponge symbiont: Citrinin, a secondary metabolite of Penicillium sp.

    PubMed Central

    Subramani, Ramesh; Kumar, Rohitesh; Prasad, Pritesh; Aalbersberg, William

    2013-01-01

    Objective To Isolate, purify, characterize, and evaluate the bioactive compounds from the sponge-derived fungus Penicillium sp. FF001 and to elucidate its structure. Methods The fungal strain FF001 with an interesting bioactivity profile was isolated from a marine Fijian sponge Melophlus sp. Based on conidiophores aggregation, conidia development and mycelia morphological characteristics, the isolate FF001 was classically identified as a Penicillium sp. The bioactive compound was identified using various spectral analysis of UV, high resolution electrospray ionization mass spectra, 1H and 13C NMR spectral data. Further minimum inhibitory concentrations (MICs) assay and brine shrimp cytotoxicity assay were also carried out to evaluate the biological properties of the purified compound. Results Bioassay guided fractionation of the EtOAc extract of a static culture of this Penicillium sp. by different chromatographic methods led the isolation of an antibacterial, anticryptococcal and cytotoxic active compound, which was identified as citrinin (1). Further, citrinin (1) is reported for its potent antibacterial activity against methicillin-resistant Staphylococcus aureus (S. aureus), rifampicin-resistant S. aureus, wild type S. aureus and vancomycin-resistant Enterococcus faecium showed MICs of 3.90, 0.97, 1.95 and 7.81 g/mL, respectively. Further citrinin (1) displayed significant activity against the pathogenic yeast Cryptococcus neoformans (MIC 3.90 g/mL), and exhibited cytotoxicity against brine shrimp larvae LD50 of 96 g/mL. Conclusions Citrinin (1) is reported from sponge associated Penicillium sp. from this study and for its strong antibacterial activity against multi-drug resistant human pathogens including cytotoxicity against brine shrimp larvae, which indicated that sponge associated Penicillium spp. are promising sources of natural bioactive metabolites. PMID:23620853

  4. Antibacterial Activity of Protocatechuic Acid Ethyl Ester on Staphylococcus aureus Clinical Strains Alone and in Combination with Antistaphylococcal Drugs.

    PubMed

    Miklasińska, Maria; Kępa, Małgorzata; Wojtyczka, Robert D; Idzik, Danuta; Zdebik, Anna; Orlewska, Kamila; Wąsik, Tomasz J

    2015-01-01

    The aim of the presented study was to examine in vitro the antibacterial activity of protocatechuic acid ethyl ester (ethyl 3,4-dihydroxybenzoate, EDHB) against Staphylococcus aureus clinical isolates alone and in the combination with four selected antibiotics. The EDHB antimicrobial activity was tested against twenty S. aureus strains isolated from the clinical samples, and three reference strains. The phenotypes and genotypes of resistance to methicillin for the tested strains were defined as well as the phenotypic resistance to macrolides, lincosamides and streptogramin B (MLSB). EDHB displayed diverse activity against examined S. aureus strains with the minimal inhibitory concentration (MIC) within the range from 64 to 1024 µg/mL. Addition of ¼ MIC of EDHB into the Mueller-Hinton Agar (MHA) resulted in augmented antibacterial effect in the presence of clindamycin. In the case of cefoxitin no synergistic effect with EDHB was noted. For erythromycin and vancomycin the decrease of mean MICs in the presence of EDHB was observed but did not reach statistical significance. The results of the present study showed that in vitro EDHB possesses antibacterial activity against S. aureus clinical strains and triggers a synergistic antimicrobial effect with clindamycin and to the lesser extent with erythromycin and vancomycin. PMID:26213908

  5. Changes of the Quinolones Resistance to Gram-positive Cocci Isolated during the Past 8 Years in the First Bethune Hospital

    NASA Astrophysics Data System (ADS)

    Xu, Jiancheng; Chen, Qihui; Yao, Hanxin; Zhou, Qi

    This study was to investigate the quinolones resistance to gram-positive cocci isolated in the First Bethune Hospital during the past 8 years. Disk diffusion test was used to study the antimicrobial resistance. The data were analyzed by WHONET 5 software according to Clinical and Laboratory Standards Institute (CLSI). The rates of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative Staphylococci (MRCNS) were 50.8%∼83.3% and 79.4%∼81.5%during the past 8 years, respectively. In recent 8 years, the quinolones resistance to gram-positive cocci had increased. Monitoring of the quinolones resistance to gram-positive cocci should be strengthened. The change of the antimicrobial resistance should be investigated in order to guide rational drug usage in the clinic and prevent bacterial strain of drug resistance from being transmitted.

  6. Design, Synthesis, Molecular Docking, and Antibacterial Evaluation of Some Novel Flouroquinolone Derivatives as Potent Antibacterial Agent

    PubMed Central

    Patel, Mehul M.; Patel, Laxman J.

    2014-01-01

    Objective. Quinolone moiety is an important class of nitrogen containing heterocycles widely used as key building blocks for medicinal agents. It exhibits a wide spectrum of pharmacophores and has bactericidal, antiviral, antimalarial, and anticancer activities. In view of the reported antimicrobial activity of various fluoroquinolones, the importance of the C-7 substituents is that they exhibit potent antimicrobial activities. Our objective was to synthesize newer quinolone analogues with increasing bulk at C-7 position of the main 6-fluoroquinolone scaffold to produce the target compounds which have potent antimicrobial activity. Methods. A novel series of 1-ethyl-6-fluoro-4-oxo-7-{4-[2-(4-substituted phenyl)-2-(substituted)-ethyl]-1-piperazinyl}-1,4-dihydroquinoline-3-carboxylic acid derivatives were synthesized. To understand the interaction of binding sites with bacterial protein receptor, the docking study was performed using topoisomerase II DNA gyrase enzymes (PDB ID: 2XCT) by Schrodinger's Maestro program. In vitro antibacterial activity of the synthesized compounds was studied and the MIC value was calculated by the broth dilution method. Results. Among all the synthesized compounds, some compounds showed potent antimicrobial activity. The compound 8g exhibited good antibacterial activity. Conclusion. This investigation identified the potent antibacterial agents against certain infections. PMID:25574496

  7. Evaluation of a topical herbal drug for its in-vivo immunomodulatory effect on cytokines production and antibacterial activity in bovine subclinical mastitis

    PubMed Central

    Bhatt, Vaibhav D.; Shah, Tejas M.; Nauriyal, Dev S.; Kunjadia, Anju P.; Joshi, Chaitanya G.

    2014-01-01

    Background: Antibiotics have been in use in the treatment of bovine mastitis since decades; however, their use is associated with cost issues and human health concern. Use of herbal drugs does not generally carry these disadvantages. Many plants/herbs have been evaluated in the treatment of bovine mastitis with additional property of immunomodulation in affected mammary gland. Aim: To evaluate a topical herbal drug in two breeds of cattle for its in-vivo immunomodulatory effect on cytokines production and antibacterial activity in bovine subclinical mastitis. Materials and Methods: The response to treatment was evaluated by enumerating somatic cell count (SCC), determining total bacterial load, and studying the expression of different cytokines (interleukin [IL]-6, IL-8, IL-12, granulocyte macrophage-colony stimulating factor, interferon (IFN)-γ and tumor necrosis factor [TNF]-α). Results: The pre- and post-treatment SCC in mastitic quarters statistically did not differ significantly, however, total bacterial load declined significantly from day 0 onwards in both the breeds. Highly significant differences (P < 0.01) were observed in all the cytokines on day 0, 5, and 21 postlast treatment in both the breeds. The expression level of all the cytokines showed a significant increase on day 5, while a decrease was noticed on day 21 in both the breeds of cattle. The comparison of cytokine expression profiles between crossbred and Gir cattle revealed a significant difference in expression of IL-6 and TNF-α. However, other cytokines exhibited a similar pattern of expression in both breeds, which was non-significant. Conclusion: The topical herbal drug exhibited antibacterial and immunomodulatory activities in subclinical mastitis and thus the work supports its use as alternative herbal therapy against subclinical udder infection in bovines. PMID:25558168

  8. Orally Bioavailable 6-Chloro-7-methoxy-4(1H)-quinolones Efficacious against Multiple Stages of Plasmodium

    PubMed Central

    2015-01-01

    The continued proliferation of malaria throughout temperate and tropical regions of the world has promoted a push for more efficacious treatments to combat the disease. Unfortunately, more recent remedies such as artemisinin combination therapies have been rendered less effective due to developing parasite resistance, and new drugs are required that target the parasite in the liver to support the disease elimination efforts. Research was initiated to revisit antimalarials developed in the 1940s and 1960s that were deemed unsuitable for use as therapeutic agents as a result of poor understanding of both physicochemical properties and parasitology. Structure–activity and structure–property relationship studies were conducted to generate a set of compounds with the general 6-chloro-7-methoxy-2-methyl-4(1H)-quinolone scaffold which were substituted at the 3-position with a variety of phenyl moieties possessing various properties. Extensive physicochemical evaluation of the quinolone series was carried out to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67, which possessed low-nanomolar EC50 values against W2 and TM90-C2B as well as improved microsomal stability. Additionally, in vivo Thompson test results using Plasmodium berghei in mice showed that these 4(1H)-quinolones were efficacious for the reduction of parasitemia at >99% after 6 days. PMID:25148516

  9. Anti-bacterial performance of azithromycin nanoparticles as colloidal drug delivery system against different gram-negative and gram-positive bacteria

    PubMed Central

    Azhdarzadeh, Morteza; Lotfipour, Farzaneh; Zakeri-Milani, Parvin; Mohammadi, Ghobad; Valizadeh, Hadi

    2012-01-01

    Purpose: Azithromycin (AZI) is a new macrolide antibiotic with a better activity against intracellular gram negative bacteria in comparison with Erythromycin. The purpose of this research was to prepare AZI nanoparticles (NPs) using PLGA polymer and to compare the effectiveness of prepared nanoparticles with untreated AZI solution. Methods: AZI NPs were prepared by Modified Quasi-Emulsion Solvent Diffusion method. The antibacterial activities of prepared NPs in comparison with AZI solution were assayed against indicator bacteria of Escherichia coli (PTCC 1330), Haemophilus influenzae (PTCC 1623) and Streptococcus pneumoniae (PTCC 1240) using agar well diffusion. Inhibition zone diameters (IZD) of nano-formulation were compared to the corresponding untreated AZI. Mean Inhibitory Concentration (MIC) values of AZI were also determined using serial dilution method in nutrient broth medium. Results: Mean IZD of nano-formulations for all indicator bacteria were significantly higher than that of untreated AZI (P<0.01). The enhanced antibacterial efficacy was more dominant in the gram positive species. The MIC values of NPs against the tested bacteria were reduced 8 times in comparison to those of untreated AZI. Conclusion: These results indicated an improved potency of AZI NPs which could be attributed to the modified surface characteristics as well as increased drug adsorption and uptake. PMID:24312766

  10. Quinolone co-resistance in ESBL- or AmpC-producing Escherichia coli from an Indian urban aquatic environment and their public health implications.

    PubMed

    Bajaj, Priyanka; Kanaujia, Pawan Kumar; Singh, Nambram Somendro; Sharma, Shalu; Kumar, Shakti; Virdi, Jugsharan Singh

    2016-01-01

    Quinolone and β-lactam antibiotics constitute major mainstay of treatment against infections caused by pathogenic Escherichia coli. Presence of E. coli strains expressing co-resistance to both these antibiotic classes in urban aquatic environments which are consistently being used for various anthropogenic activities represents a serious public health concern. From a heterogeneous collection of 61 E. coli strains isolated from the river Yamuna traversing through the National Capital Territory of Delhi (India), those harboring blaCTX-M-15 (n = 10) or blaCMY-42 (n = 2) were investigated for co-resistance to quinolones and the molecular mechanisms thereof. Resistance was primarily attributed to amino acid substitutions in the quinolone resistance-determining regions (QRDRs) of GyrA (S83L ± D87N) and ParC (S80I ± E84K). One of the E. coli strains, viz., IPE, also carried substitutions in GyrB and ParE at positions Ser492→Asn and Ser458→Ala, respectively. The phenotypically susceptible strains nevertheless carried plasmid-mediated quinolone resistance (PMQR) gene, viz., qnrS, which showed co-transfer to the recipient quinolone-sensitive E. coli J53 along with the genes encoding β-lactamases and led to increase in minimal inhibitory concentrations of quinolone antibiotics. To the best of our knowledge, this represents first report of molecular characterization of quinolone co-resistance in E. coli harboring genes for ESBLs or AmpC β-lactamases from a natural aquatic environment of India. The study warrants true appreciation of the potential of urban aquatic environments in the emergence and spread of multi-drug resistance and underscores the need to characterize resistance genetic elements vis-à-vis their public health implications, irrespective of apparent phenotypic resistance. PMID:26498967

  11. Antibacterial and antibiotic-potentiation activities of the methanol extract of some cameroonian spices against Gram-negative multi-drug resistant phenotypes

    PubMed Central

    2012-01-01

    Background The present work was designed to evaluate the antibacterial properties of the methanol extracts of eleven selected Cameroonian spices on multi-drug resistant bacteria (MDR), and their ability to potentiate the effect of some common antibiotics used in therapy. Results The extract of Cinnamomum zeylanicum against Escherichia coli ATCC 8739 and AG100 strains showed the best activities, with the lowest minimal inhibitory concentration (MIC) of 64 μg/ml. The extract of Dorstenia psilurus was the most active when tested in the presence of an efflux pump inhibitor, phenylalanine Arginine-β- Naphtylamide (PAβN), a synergistic effect being observed in 56.25 % of the tested bacteria when it was combined with Erythromycin (ERY). Conclusion The present work evidently provides information on the role of some Cameroonian spices in the fight against multi-resistant bacteria. PMID:22709668

  12. In vitro interaction of antifungal and antibacterial drugs against Cryptococcus neoformans var. grubii before and after capsular induction.

    PubMed

    Rossato, Luana; Loreto, Érico S; Venturini, Tarcieli P; Azevedo, Maria I; Weiblen, Carla; Botton, Sonia A; Santurio, Janio M; Alves, Sydney H

    2015-11-01

    This study evaluated the synergistic interactions between amphotericin B (AMB) and azithromycin (AZM), daptomycin (DAP), linezolid (LNZ), minocycline (MINO), fluconazole (FLZ), flucytosine (5FC), linezolid (LZD), or tigecycline (TIG) against clinical isolates of Cryptococcus neoformans var. grubii before and after capsule induction. High synergism (>75%) was observed for the combinations, AMB+5FC, AMB+TIG, AMB+AZM, AMB+LZD and AMB+MINO but only in the strains after capsule induction. The results show that the presence of the capsule may lower the minimum inhibitory concentrations (MICs) of antifungal agents, but antimicrobial activity can be improved by combining antifungal and antibacterial agents. PMID:26333356

  13. [Residues of tetracycline and quinolones in wild fish living around a salmon aquaculture center in Chile].

    PubMed

    Fortt Z, Antonia; Cabello C, Felipe; Buschmann R, Alejandro

    2007-02-01

    The presence of residues of tetracycline, quinolones and antiparasitic drugs was investigated in wild fish captured around salmon aquaculture pens in Cochamó, Region X, Chile. Residues of both antibiotics were found in the meta [corrected] of two species of wild fish that are consumed by humans, robalo (Elginops maclovinus) and cabrilla (Sebastes capensis) [corrected] These findings suggest that the antibiotic usage in salmon aquaculture in Chile has nvironmental implications that may affect human and animal health. More studies are needed in Chile to determine the relevance of these findings for human and animal health and the environment to regulate this use of antibiotics. PMID:17369965

  14. Quinolone resistance mediated by norA: physiologic characterization and relationship to flqB, a quinolone resistance locus on the Staphylococcus aureus chromosome.

    PubMed

    Ng, E Y; Trucksis, M; Hooper, D C

    1994-06-01

    We identified a quinolone resistance locus, flqB, linked to transposon insertion omega 1108 and fus on the SmaI D fragment of the Staphylococcus aureus NCTC 8325 chromosome, the same fragment that contains the norA gene. S. aureus norA cloned from flqB and flqB+ strains in Escherichia coli differed only in a single nucleotide in the putative promoter region. There was no detectable change in the number of copies of norA on the chromosomes of flqB strains, but they had increased levels of norA transcripts. Cloned norA produced resistance to norfloxacin and other hydrophilic quinolones and reduced norfloxacin accumulation in intact cells that was energy dependent, suggesting active drug efflux as the mechanism of resistance. Drug efflux was studied by measurement of norfloxacin uptake into everted inner membrane vesicles prepared from norA-containing E. coli cells. Vesicles exhibited norfloxacin uptake after the addition of lactate or NADH, and this uptake was abolished by carbonyl cyanide m-chlorophenylhydrazone and nigericin but not valinomycin, indicating that it was linked to the pH gradient across the cell membrane. Norfloxacin uptake into vesicles was also saturable, with an apparent Km of 6 microM, a concentration between those that inhibit the growth of flqB and flqB+ S. aureus cells, indicating that drug uptake is mediated by a carrier with a high apparent affinity for norfloxacin. Ciprofloxacin and ofloxacin competitively inhibited norfloxacin uptake into vesicles. Reserpine, which inhibits the multidrug efflux mediated by the bmr gene of bacillus subtilis, which is similar to norA, abolished norfloxacin uptake into vesicles as well as the norfloxacin resistance of an flqB mutant, suggesting a potential means for circumventing quinolone resistance as a result of drug efflux in S. aureus. These findings indicate that the chromosomal flqB resistance locus is associated with increased levels of expression of norA and strongly suggest that the NorA protein itself functions as a drug transporter that is coupled to the proton gradient across the cell membrane. PMID:8092836

  15. Differences in susceptibility to quinolones of outer membrane mutants of Salmonella typhimurium and Escherichia coli.

    PubMed Central

    Hirai, K; Aoyama, H; Irikura, T; Iyobe, S; Mitsuhashi, S

    1986-01-01

    The mechanism of penetration of quinolones through the bacterial outer membrane was studied with lipopolysaccharide-deficient and porin-deficient mutants. The data indicated that the lipopolysaccharide layer might form a permeability barrier for hydrophobic quinolones such as nalidixic acid but not for hydrophilic quinolones such as norfloxacin and ciprofloxacin. The results also showed that quinolones with a low relative hydrophobicity appeared to permeate through OmpF porin, whereas quinolones with a low relative hydrophobicity appeared to permeate through OmpF porin, whereas quinolones with a high relative hydrophobicity appeared to permeate through both OmpF porin and phospholipid bilayers. PMID:3521490

  16. Monte Carlo simulation for evaluation of the efficacy of carbapenems and new quinolones against ESBL-producing Escherichia coli.

    PubMed

    Nakamura, Tatsuya; Shimizu, Chihiro; Kasahara, Mayumi; Okuda, Kazuyuki; Nakata, Chiyo; Fujimoto, Hiroko; Okura, Hiroe; Komatsu, Masaru; Shimakawa, Kouichi; Sueyoshi, Noriyuki; Ura, Toshiro; Satoh, Kaori; Toyokawa, Masahiro; Wada, Yasunao; Orita, Tamaki; Kofuku, Tomomi; Yamasaki, Katsutoshi; Sakamoto, Masako; Nishio, Hisaaki; Kinoshita, Shohiro; Takahashi, Hakuo

    2009-02-01

    Extended-spectrum beta-lactamase (ESBL)-producing bacteria are known to be resistant to penicillins, cephalosporins, and monobactams because of their substrate specificity, and these bacteria are sensitive only to a narrow range of antimicrobial agents. The present study was undertaken to evaluate the efficacy of carbapenems and the new quinolones against ESBL-producing Escherichia coli, using a Monte Carlo simulation based on the pharmacokinetic/pharmacodynamic (PK/PD) theory. The time above MIC (TAM, %) served as the PK/PD parameter for carbapenems, with the target level set at 40%. The AUC/MIC served as the PK/PD parameter for the new quinolones, with the target level set at more than 125. In the analysis of drug sensitivity, the MIC50 of all carbapenems other than imipenem was low (0.03 microg/ml), while the MIC50 of the new quinolones was higher (1-2 microg/ml). The probability of achieving the PK/PD target with carba penems after two doses at the usual dose level, as determined by the Monte Carlo simulation, was high for each of the carbapenems tested (99.0% for biapenem, 99.60% for meropenem, and 95.03% for doripenem), except for imipenem. Among the new quinolones, the highest probability of achieving the PK/PD target was obtained with pazufloxacin (42.90%). Thus, the results of the present study have revealed that carbapenems are effective at the regular dose and can be used as the first-choice antibiotics for ESBL-producing E. coli because the resistance ratios for carbapenems are low compared to those of the new quinolones. PMID:19280294

  17. Phase composition control of calcium phosphate nanoparticles for tunable drug delivery kinetics and treatment of osteomyelitis. II. Antibacterial and osteoblastic response.

    PubMed

    Uskokovi?, Vuk; Desai, Tejal A

    2013-05-01

    Osteomyelitis has been traditionally treated by the combination of long-term antibiotic therapies and surgical removal of diseased tissue. The multifunctional material was developed in this study with the aim to improve this therapeutic approach by: (a) enabling locally delivered and sustained release of antibiotics at a tunable rate, so as to eliminate the need for repetitive administration of systemically distributed antibiotics; and (b) controllably dissolving itself, so as to promote natural remineralization of the portion of bone lost to disease. We report hereby on the effect of previously synthesized calcium phosphates (CAPs) with tunable solubilities and drug release timescales on bacterial and osteoblastic cell cultures. All CAP powders exhibited satisfying antibacterial performance against Staphylococcus aureus, the main causative agent of osteomyelitis. Still, owing to its highest drug adsorption efficiency, the most bacteriostatically effective phase was amorphous CAP with the minimal inhibitory concentration of less than 1 mg/mL. At the same time, the positive cell response and osteogenic effect of the antibiotic-loaded CAP particles was confirmed in vitro for all the sparsely soluble CAP phases. Adsorption of the antibiotic onto CAP particles reversed the deleterious effect that the pure antibiotic exerted on the osteogenic activity of the osteoblastic cells. The simultaneous osteogenic and antimicrobial performance of the material developed in this study, altogether with its ability to exhibit sustained drug release, may favor its consideration as a material base for alternative therapeutic approaches to prolonged antibiotic administration and surgical debridement typically prescribed in the treatment of osteomyelitis. PMID:23115128

  18. Phase Composition Control of Calcium Phosphate Nanoparticles for Tunable Drug Delivery Kinetics and Treatment of Osteomyelitis. Part 2: Antibacterial and Osteoblastic Response

    PubMed Central

    Uskoković, Vuk; Desai, Tejal A.

    2012-01-01

    Osteomyelitis has been traditionally treated by the combination of long-term antibiotic therapies and surgical removal of diseased tissue. The multifunctional material was developed in this study with the aim to improve this therapeutic approach by: (a) enabling locally delivered and sustained release of antibiotics at a tunable rate, so as to eliminate the need for repetitive administration of systemically distributed antibiotics; and (b) controllably dissolving itself, so as to promote natural remineralization of the portion of bone lost to disease. We report hereby on the effect of the previously synthesized calcium phosphates (CAPs) with tunable solubilities and drug release time scales on bacterial and osteoblastic cell cultures. All CAP powders exhibited satisfying antibacterial performance against Staphylococcus aureus, the main causative agent of osteomyelitis. Still, owing to its highest drug adsorption efficiency, the most bacteriostatically effective phase was amorphous CAP with the minimal inhibitory concentration of less than 1 mg/ml. At the same time, the positive cell response and osteogenic effect of the antibiotic-loaded CAP particles was confirmed in vitro for all the sparsely soluble CAP phases. Adsorption of the antibiotic onto CAP particles reversed the deleterious effect that the pure antibiotic exerted on the osteogenic activity of the osteoblastic cells. The simultaneous osteogenic and antimicrobial performance of the material developed in this study, altogether with its ability to exhibit sustained drug release, may favor its consideration as a material base for alternative therapeutic approaches to prolonged antibiotic administration and surgical debridement typically prescribed in the treatment of osteomyelitis. PMID:23115128

  19. Palladium(II) complexes as biologically potent metallo-drugs: Synthesis, spectral characterization, DNA interaction studies and antibacterial activity

    NASA Astrophysics Data System (ADS)

    Prasad, Kollur Shiva; Kumar, Linganna Shiva; Chandan, Shivamallu; Naveen Kumar, R. M.; Revanasiddappa, Hosakere D.

    2013-04-01

    Four novel mononuclear Pd(II) complexes have been synthesized with the biologically active Schiff base ligands (L1-L4) derived from 3-amino-2-methyl-4(3H)-quinazolinone. The structure of the complexes has been proposed by elemental analysis, molar conductance, IR, 1H NMR, mass, UV-Vis spectrometric and thermal studies. The investigation of interaction of the complexes with calf thymus DNA (CT-DNA) has been performed with absorption and fluorescence spectroscopic studies. The nuclease activity was done using pUC19 supercoiled DNA by gel-electrophoresis. All the ligands and their Pd(II) complexes have also been screened for their antibacterial activity by discolor diffusion technique.

  20. Antibacterials from the Sea

    PubMed Central

    Hughes, Chambers C.; Fenical, William

    2011-01-01

    The ocean contains a host of macroscopic life in a great microbial soup. Unlike the terrestrial environment, an aqueous environment provides perpetual propinquity and blurs spatial distinctions. Marine organisms are under a persistent threat of infection by resident pathogenic microbes including bacteria, and in response they have engineered complex organic compounds with antibacterial activity from a diverse set of biological precursors. The diluting effect of the ocean drives the construction of potent molecules that are stable to harsh salty conditions. Members of each class of metabolite—ribosomal and non-ribosomal peptides, alkaloids, polyketides, and terpenes—have been shown to exhibit antibacterial activity. The sophistication and diversity of these metabolites points to the ingenuity and flexibility of biosynthetic processes in Nature. Compared with their terrestrial counterparts, antibacterial marine natural products have received much less attention. Thus, a concerted effort to discover new antibacterials from marine sources has the potential to contribute significantly to the treatment of the ever increasing drug-resistant infectious diseases. PMID:20845412

  1. Three-dimensional structures of unligated uridine phosphorylase from Yersinia pseudotuberculosis at 1.4 Å resolution and its complex with an antibacterial drug

    NASA Astrophysics Data System (ADS)

    Balaev, V. V.; Lashkov, A. A.; Gabdulkhakov, A. G.; Dontsova, M. V.; Mironov, A. S.; Betzel, C.; Mikhailov, A. M.

    2015-07-01

    Uridine phosphorylases play an essential role in the cellular metabolism of some antibacterial agents. Acute infectious diseases (bubonic plague, yersiniosis, pseudotuberculosis, etc., caused by bacteria of the genus Yersinia) are treated using both sulfanilamide medicines and antibiotics, including trimethoprim. The action of an antibiotic on a bacterial cell is determined primarily by the character of its interactions with cellular components, including those which are not targets (for example, with pyrimidine phosphorylases). This type of interaction should be taken into account in designing drugs. The three-dimensional structure of uridine phosphorylase from the bacterium Yersinia pseudotuberculosis ( YptUPh) with the free active site was determined for the first time by X-ray crystallography and refined at 1.40 Å resolution (DPI = 0.062 Å; ID PDB: 4OF4). The structure of the complex of YptUPh with the bacteriostatic drug trimethoprim was studied by molecular docking and molecular dynamics methods. The trimethoprim molecule was shown to be buffered by the enzyme YptUPh, resulting in a decrease in the efficiency of the treatment of infectious diseases caused by bacteria of the genus Yersinia with trimethoprim.

  2. Chemoinformatics for rational discovery of safe antibacterial drugs: simultaneous predictions of biological activity against streptococci and toxicological profiles in laboratory animals.

    PubMed

    Speck-Planche, Alejandro; Kleandrova, Valeria V; Cordeiro, M N D S

    2013-05-15

    Streptococci are a group of Gram-positive bacteria which are responsible for causing many diverse diseases in humans and other animals worldwide. The high prevalence of resistance of these bacteria to current antibacterial drugs is an alarming problem for the scientific community. The battle against streptococci by using antimicrobial chemotherapies will depend on the design of new chemicals with high inhibitory activity, having also as low toxicity as possible. Multi-target approaches based on quantitative-structure activity relationships (mt-QSAR) have played a very important role, providing a better knowledge about the molecular patterns related with the appearance of different pharmacological profiles including antimicrobial activity. Until now, almost all mt-QSAR models have considered the study of biological activity or toxicity separately. In the present study, we develop by the first time, a unified multitasking (mtk) QSAR model for the simultaneous prediction of anti-streptococci activity and toxic effects against biological models like Mus musculus and Rattus norvegicus. The mtk-QSAR model was created by using artificial neural networks (ANN) analysis for the classification of compounds as positive (high biological activity and/or low toxicity) or negative (otherwise) under diverse sets of experimental conditions. Our mtk-QSAR model, correctly classified more than 97% of the cases in the whole database (more than 11,500 cases), serving as a promising tool for the virtual screening of potent and safe anti-streptococci drugs. PMID:23582445

  3. Anti-inflammatory drugs interacting with Zn (II) metal ion based on thiocyanate and azide ligands: Synthesis, spectroscopic studies, DFT calculations and antibacterial assays

    NASA Astrophysics Data System (ADS)

    Chiniforoshan, Hossein; Tabrizi, Leila; Hadizade, Morteza; Sabzalian, Mohammad R.; Chermahini, Alireza Najafi; Rezapour, Mehdi

    2014-07-01

    Zinc (II) complexes with non-steroidal anti-inflammatory drugs (NSAIDs) naproxen (nap) and ibuprofen (ibu) were synthesized in the presence of nitrogen donor ligands (thiocyanate or azide). The complexes were characterized by elemental analysis, FT-IR, 1H NMR and UV-Vis spectroscopes. The binding modes of the ligands in complexes were established by means of molecular modeling of the complexes, and calculation of their IR, NMR and absorption spectra at DFT (TDDFT)/B3LYP level were studied. The experimental and calculated data verified monodentate binding through the carboxylic oxygen atoms of anti-inflammatory drugs in the zinc complexes. The calculated 1H, FT-IR and UV-Vis data are in better agreement with the experimental results, and confirm the predicted tetrahedral structures for the Zn (II) complexes. In addition to DFT calculations of complexes, natural bond orbital (NBO) was performed at B3LYP/6-31+G(d,p) level of theory. Biological studies showed the antibacterial activity of zinc complexes against Gram-positive and Gram-negative bacterial strains.

  4. Determination of quinolones in water samples by solid-phase extraction and liquid chromatography with fluorimetric detection.

    PubMed

    Prat, M D; Benito, J; Compañó, R; Hernández-Arteseros, J A; Granados, M

    2004-07-01

    A method is reported for the determination, in water samples, of 10 quinolones which are used as veterinary drugs. Analytes are isolated from samples by solid-phase extraction (SPE) and analysed by reversed-phase high-performance liquid chromatography using fluorimetric detection. A solid-phase extraction procedure based on retention on HBL OASIS cartridges and elution with a mixture of acetonitrile-water in basic medium is suitable for pre-concentration of the analytes. Pre-concentration factors up to 250 can be obtained. The quinolones are separated with an octyl silica-based column and mobile phases consisting of aqueous oxalic acid solutions and acetonitrile mixtures. The attained detection limits of the whole process are in the ng l(-1) level when 250 ml of water sample is processed. Recovery rates, from natural water samples spiked at 2060 ng l(-1) level, range from 70 to 100% and common standard deviation are about 6-12%. PMID:15281251

  5. Quinolone antibiotics in therapy of experimental pneumococcal meningitis in rabbits.

    PubMed Central

    Nau, R; Schmidt, T; Kaye, K; Froula, J L; Täuber, M G

    1995-01-01

    Using a rabbit model of pneumococcal meningitis, we compared the pharmacokinetics and bactericidal activities in cerebrospinal fluid (CSF) of older (ciprofloxacin, ofloxacin) and newer (levofloxacin, temafloxacin, CP-116,517, and Win 57273) quinolones with those of the beta-lactam ceftriaxone. All quinolones penetrated into the inflamed CSF better than ceftriaxone, and the speed of entry into CSF was closely related to their degrees of lipophilicity. At a dose of 10 mg/kg.h, which in the case of the quinolones already in use in clinical practice produced concentrations attainable in the sera and CSF of humans, ciprofloxacin had no antipneumococcal activity (delta log10 CFU/ml.h, +0.20 +/- 0.14). Ofloxacin (delta log10 CFU/ml.h, -0.13 +/- 0.12), temafloxacin (delta log10 CFU/ml.h, -0.19 +/- 0.18), and levofloxacin (delta log10 CFU/ml.h, -0.24 +/- 0.16) showed slow bactericidal activity (not significantly different from each other), while CP-116,517 (delta log10 CFU/ml.h, -0.59 +/- 0.21) and Win 57273 (delta log10 CFU/ml.h, -0.72 +/- 0.20) showed increased bactericidal activities in CSF that was comparable to that of ceftriaxone at 10 mg/kg.h (delta log10 CFU/ml.h, -0.80 +/- 0.17). These improved in vivo activities of the newer quinolones reflected their increased in vitro activities. All quinolones and ceftriaxone showed positive correlations between bactericidal rates in CSF and concentrations in CSF relative to their MBCs. Only when this ratio exceeded 10 did the antibiotics exhibit rapid bactericidal activities in CSF. In conclusion, in experimental pneumococcal meningitis the activities of new quinolones with improved antipneumococcal activities were comparable to that of ceftriaxone. PMID:7793857

  6. Characterisation of novel mutations involved in quinolone resistance in Escherichia coli isolated from imported shrimp.

    PubMed

    Nawaz, Mohamed; Sung, Kidon; Kweon, Ohgew; Khan, Saeed; Nawaz, Samia; Steele, Roger

    2015-05-01

    Fifty-five nalidixic acid-resistant Escherichia coli strains were isolated from imported shrimp. Purified PCR amplicons of gyrA, gyrB, parC and parE from the template DNA of all isolates were sequenced and analysed for point mutations that confer resistance to nalidixic acid and ciprofloxacin. Point mutations in the quinolone resistance-determining regions (QRDRs) of GyrA at positions 68, 83 and 87 and in ParC at positions 80 and 84 as well as in the non-QRDR of GyrA at positions 112, 127, 128 and 154 along with point mutations in parE at position 476 conferred resistance to these antibiotics. Computational modelling and analysis of the different point mutations and their role in the enhanced resistance to these antibiotics indicated that only mutation at codons 83 (Ser→Ile) and 87 (Asp→Asn) played a vital role in increasing the minimum inhibitory concentration (MIC) to these drugs compared with other mutations. Ethidium bromide experiments indicated higher efflux pump activities in quinolone-resistant E. coli strains compared with their quinolone-sensitive counterparts. Class 1 integrons measuring 0.7-2.3kb were amplified and sequenced from the template DNA of the isolates. Sequence analysis of the 2.0kb and 1.7kb integrons indicated the presence of resistance determinants for trimethoprim (dfrA12 and dfrA17) and aminoglycosides (aadA2 and aadA5). These results indicate that use of nalidixic acid, ciprofloxacin and other antibiotics in shrimp aquaculture ponds may select E. coli resistant to these antibiotics and that imported shrimp is a reservoir of multiple antibiotic-resistant E. coli. PMID:25631675

  7. Morphology, drug release, antibacterial, cell proliferation, and histology studies of chamomile-loaded wound dressing mats based on electrospun nanofibrous poly(ɛ-caprolactone)/polystyrene blends.

    PubMed

    Motealleh, Behrooz; Zahedi, Payam; Rezaeian, Iraj; Moghimi, Morvarid; Abdolghaffari, Amir Hossein; Zarandi, Mohammad Amin

    2014-07-01

    For the first time, it has been tried to achieve optimum conditions for electrospun poly(ε-caprolactone)/polystyrene (PCL/PS) nanofibrous samples as active wound dressings containing chamomile via D-optimal design approach. In this work, systematic in vitro and in vivo studies were carried out by drug release rate, antibacterial and antifungal evaluations, cell culture, and rat wound model along with histology observation. The optimized samples were prepared under the following electrospinning conditions: PCL/PS ratio (65/35), PCL concentration 9%(w/v), PS concentration 14%(w/v), distance between the syringe needle tip and the collector 15.5 cm, applied voltage 18 kV, and solution flow rate 0.46 mL h(-1) . The FE-SEM micrographs showed electrospun PCL/PS (65/35) nanofibrous sample containing 15% chamomile had a minimum average diameter (∼175 nm) compared to the neat samples (∼268 nm). The drug released resulted in a gradual and high amount of chamomile from the optimized PCL/PS nanofibrous sample (∼70%) in respect to PCL and PS nanofibers after 48 h. This claim was also confirmed by antibacterial and antifungal evaluations in which an inhibitory zone with a diameter of about 7.6 mm was formed. The rat wound model results also indicated that the samples loaded with 15% chamomile extract were remarkably capable to heal the wounds up to 99 ± 0.5% after 14 days post-treatment periods. The adhesion of mesenchymal stem cells and their viability on the optimized samples were confirmed by MTT analysis. Also, the electrospun nanofibrous mats based on PCL/PS (65/35) showed a high efficiency in the wound closure and healing process compared to the reference sample, PCL/PS nanofibers without chamomile. Finally, the histology analysis revealed that the formation of epithelial tissues, the lack of necrosis and collagen fibers accumulation in the dermis tissues for the above optimized samples. PMID:24259351

  8. Antistaphylococcal Activity of DX-619, a New Des-F(6)-Quinolone, Compared to Those of Other Agents

    PubMed Central

    Bogdanovich, Tatiana; Esel, Duygu; Kelly, Linda M.; Bozdogan, Blent; Credito, Kim; Lin, Gengrong; Smith, Kathy; Ednie, Lois M.; Hoellman, Dianne B.; Appelbaum, Peter C.

    2005-01-01

    The in vitro activity of DX-619, a new des-F(6)-quinolone, was tested against staphylococci and compared to those of other antimicrobials. DX-619 had the lowest MIC ranges/MIC50s/MIC90s (?g/ml) against 131 Staphylococcus aureus strains (?0.002 to 2.0/0.06/0.5) and 128 coagulase-negative staphylococci (0.004 to 0.25/0.016/0.125). Among strains tested, 76 S. aureus strains and 51 coagulase-negative staphylococci were resistant to ciprofloxacin. DX-619 had the lowest MIC50/MIC90 values against 127 quinolone-resistant staphylococci (0.125/0.5), followed by sitafloxacin (0.5/4), moxifloxacin (2/8), gatifloxacin (4/16), levofloxacin (16/>32), and ciprofloxacin (>32/>32). Raised quinolone MICs were associated with mutations in GyrA (S84L) and single or double mutations in GrlA (S80F or Y; E84K, G, or V) in all S. aureus strains tested. A recent vancomycin-resistant S. aureus (VRSA) strain (Hershey) was resistant to available quinolones and was inhibited by DX-619 at 0.25 ?g/ml and sitafloxacin at 1.0 ?g/ml. Vancomycin (except VRSA), linezolid, ranbezolid, tigecycline, and quinupristin-dalfopristin were active against all strains, and teicoplanin was active against S. aureus but less active against coagulase-negative staphylococci. DX-619 produced resistant mutants with MICs of 1 to >32 ?g/ml after <50 days of selection compared to 16 to >32 ?g/ml for ciprofloxacin, sitafloxacin, moxifloxacin, and gatifloxacin. DX-619 and sitafloxacin were also more active than other tested drugs against selected mutants and had the lowest mutation frequencies in single-step resistance selection. DX-619 and sitafloxacin were bactericidal against six quinolone-resistant (including the VRSA) and seven quinolone-susceptible strains tested, whereas gatifloxacin, moxifloxacin, levofloxacin, and ciprofloxacin were bactericidal against 11, 10, 7, and 5 strains at 4 MIC after 24 h, respectively. DX-619 was also bactericidal against one other VRSA strain, five vancomycin-intermediate S. aureus strains, and four vancomycin-intermediate coagulase-negative staphylococci. Linezolid, ranbezolid, and tigecycline were bacteriostatic and quinupristin-dalfopristin, teicoplanin, and vancomycin were bactericidal against two, eight, and nine strains, and daptomycin and oritavancin were rapidly bactericidal against all strains, including the VRSA. DX-619 has potent in vitro activity against staphylococci, including methicillin-, ciprofloxacin-, and vancomycin-resistant strains. PMID:16048943

  9. Antistaphylococcal activity of DX-619, a new des-F(6)-quinolone, compared to those of other agents.

    PubMed

    Bogdanovich, Tatiana; Esel, Duygu; Kelly, Linda M; Bozdogan, Blent; Credito, Kim; Lin, Gengrong; Smith, Kathy; Ednie, Lois M; Hoellman, Dianne B; Appelbaum, Peter C

    2005-08-01

    The in vitro activity of DX-619, a new des-F(6)-quinolone, was tested against staphylococci and compared to those of other antimicrobials. DX-619 had the lowest MIC ranges/MIC(50)s/MIC(90)s (microg/ml) against 131 Staphylococcus aureus strains (quinolone-resistant staphylococci (0.125/0.5), followed by sitafloxacin (0.5/4), moxifloxacin (2/8), gatifloxacin (4/16), levofloxacin (16/>32), and ciprofloxacin (>32/>32). Raised quinolone MICs were associated with mutations in GyrA (S84L) and single or double mutations in GrlA (S80F or Y; E84K, G, or V) in all S. aureus strains tested. A recent vancomycin-resistant S. aureus (VRSA) strain (Hershey) was resistant to available quinolones and was inhibited by DX-619 at 0.25 microg/ml and sitafloxacin at 1.0 microg/ml. Vancomycin (except VRSA), linezolid, ranbezolid, tigecycline, and quinupristin-dalfopristin were active against all strains, and teicoplanin was active against S. aureus but less active against coagulase-negative staphylococci. DX-619 produced resistant mutants with MICs of 1 to >32 microg/ml after <50 days of selection compared to 16 to >32 microg/ml for ciprofloxacin, sitafloxacin, moxifloxacin, and gatifloxacin. DX-619 and sitafloxacin were also more active than other tested drugs against selected mutants and had the lowest mutation frequencies in single-step resistance selection. DX-619 and sitafloxacin were bactericidal against six quinolone-resistant (including the VRSA) and seven quinolone-susceptible strains tested, whereas gatifloxacin, moxifloxacin, levofloxacin, and ciprofloxacin were bactericidal against 11, 10, 7, and 5 strains at 4x MIC after 24 h, respectively. DX-619 was also bactericidal against one other VRSA strain, five vancomycin-intermediate S. aureus strains, and four vancomycin-intermediate coagulase-negative staphylococci. Linezolid, ranbezolid, and tigecycline were bacteriostatic and quinupristin-dalfopristin, teicoplanin, and vancomycin were bactericidal against two, eight, and nine strains, and daptomycin and oritavancin were rapidly bactericidal against all strains, including the VRSA. DX-619 has potent in vitro activity against staphylococci, including methicillin-, ciprofloxacin-, and vancomycin-resistant strains. PMID:16048943

  10. Antibacterial Applications of Nanodiamonds

    PubMed Central

    Szunerits, Sabine; Barras, Alexandre; Boukherroub, Rabah

    2016-01-01

    Bacterial infectious diseases, sharing clinical characteristics such as chronic inflammation and tissue damage, pose a major threat to human health. The steady increase of multidrug-resistant bacteria infections adds up to the current problems modern healthcare is facing. The treatment of bacterial infections with multi-resistant germs is very difficult, as the development of new antimicrobial drugs is hardly catching up with the development of antibiotic resistant pathogens. These and other considerations have generated an increased interest in the development of viable alternatives to antibiotics. A promising strategy is the use of nanomaterials with antibacterial character and of nanostructures displaying anti-adhesive activity against biofilms. Glycan-modified nanodiamonds (NDs) revealed themselves to be of great promise as useful nanostructures for combating microbial infections. This review summarizes the current efforts in the synthesis of glycan-modified ND particles and evaluation of their antibacterial and anti-biofilm activities. PMID:27077871

  11. Antibacterial Applications of Nanodiamonds.

    PubMed

    Szunerits, Sabine; Barras, Alexandre; Boukherroub, Rabah

    2016-01-01

    Bacterial infectious diseases, sharing clinical characteristics such as chronic inflammation and tissue damage, pose a major threat to human health. The steady increase of multidrug-resistant bacteria infections adds up to the current problems modern healthcare is facing. The treatment of bacterial infections with multi-resistant germs is very difficult, as the development of new antimicrobial drugs is hardly catching up with the development of antibiotic resistant pathogens. These and other considerations have generated an increased interest in the development of viable alternatives to antibiotics. A promising strategy is the use of nanomaterials with antibacterial character and of nanostructures displaying anti-adhesive activity against biofilms. Glycan-modified nanodiamonds (NDs) revealed themselves to be of great promise as useful nanostructures for combating microbial infections. This review summarizes the current efforts in the synthesis of glycan-modified ND particles and evaluation of their antibacterial and anti-biofilm activities. PMID:27077871

  12. Challenges of Antibacterial Discovery

    PubMed Central

    Silver, Lynn L.

    2011-01-01

    Summary: The discovery of novel small-molecule antibacterial drugs has been stalled for many years. The purpose of this review is to underscore and illustrate those scientific problems unique to the discovery and optimization of novel antibacterial agents that have adversely affected the output of the effort. The major challenges fall into two areas: (i) proper target selection, particularly the necessity of pursuing molecular targets that are not prone to rapid resistance development, and (ii) improvement of chemical libraries to overcome limitations of diversity, especially that which is necessary to overcome barriers to bacterial entry and proclivity to be effluxed, especially in Gram-negative organisms. Failure to address these problems has led to a great deal of misdirected effort. PMID:21233508

  13. 4-quinolone signalling in Pseudomonas aeruginosa: old molecules, new perspectives.

    PubMed

    Diggle, Stephen P; Cornelis, Pierre; Williams, Paul; Cámara, Miguel

    2006-04-01

    In Pseudomonas aeruginosa, diverse virulence determinants and secondary metabolites are regulated via the action of a hierarchical quorum-sensing system which integrates two chemically distinct classes of signal molecules, the N-acylhomoserine lactones (AHLs) and the 4-quinolones (4Qs). Synthesis of the pseudomonas quinolone signal, 2-heptyl-3-hydroxy-4-quinolone (PQS) depends on the pqsABCDE locus which is responsible for generating multiple 4Qs including 2-heptyl-4-quinolone (HHQ), the immediate PQS precursor. Exported HHQ is taken up by adjacent bacterial cells and converted into PQS by PqsH, a putative mono-oxygenase. In addition, PQS regulates its own production by driving the expression of pqsABCDE through a direct interaction with PqsR (MvfR). PQS regulates diverse target genes including those coding for elastase, rhamnolipid, the PA-IL lectin and pyocyanin via the action of PqsE as well as influencing biofilm development and impacting on cellular fitness. Furthermore, 4Q signalling is not restricted to P. aeruginosa raising the possibility of cross-talk with other related bacterial species which occupy similar ecological niches. PMID:16483840

  14. Antibacterial Activity of Novel Cationic Peptides against Clinical Isolates of Multi-Drug Resistant Staphylococcus pseudintermedius from Infected Dogs

    PubMed Central

    Mohamed, Mohamed F.; Hammac, G. Kenitra; Guptill, Lynn; Seleem, Mohamed N.

    2014-01-01

    Staphylococcus pseudintermedius is a major cause of skin and soft tissue infections in companion animals and has zoonotic potential. Additionally, methicillin-resistant S. pseudintermedius (MRSP) has emerged with resistance to virtually all classes of antimicrobials. Thus, novel treatment options with new modes of action are required. Here, we investigated the antimicrobial activity of six synthetic short peptides against clinical isolates of methicillin-susceptible and MRSP isolated from infected dogs. All six peptides demonstrated potent anti-staphylococcal activity regardless of existing resistance phenotype. The most effective peptides were RRIKA (with modified C terminus to increase amphipathicity and hydrophobicity) and WR-12 (?-helical peptide consisting exclusively of arginine and tryptophan) with minimum inhibitory concentration50 (MIC50) of 1 M and MIC90 of 2 M. RR (short anti-inflammatory peptide) and IK8 D isoform demonstrated good antimicrobial activity with MIC50 of 4 M and MIC90 of 8 M. Penetratin and (KFF)3K (two cell penetrating peptides) were the least effective with MIC50 of 8 M and MIC90 of 16 M. Killing kinetics revealed a major advantage of peptides over conventional antibiotics, demonstrating potent bactericidal activity within minutes. Studies with propidium iodide and transmission electron microscopy revealed that peptides damaged the bacterial membrane leading to leakage of cytoplasmic contents and consequently, cell death. A potent synergistic increase in the antibacterial effect of the cell penetrating peptide (KFF)3K was noticed when combined with other peptides and with antibiotics. In addition, all peptides displayed synergistic interactions when combined together. Furthermore, peptides demonstrated good therapeutic indices with minimal toxicity toward mammalian cells. Resistance to peptides did not evolve after 10 passages of S. pseudintermedius at sub-inhibitory concentration. However, the MICs of amikacin and ciprofloxacin increased 32 and 8 fold, respectively; under similar conditions. Taken together, these results support designing of peptide-based therapeutics for combating MRSP infections, particularly for topical application. PMID:25551573

  15. Electrochemical evaluation of antibacterial drugs as environment-friendly inhibitors for corrosion of carbon steel in HCl solution

    NASA Astrophysics Data System (ADS)

    Golestani, Gh.; Shahidi, M.; Ghazanfari, D.

    2014-07-01

    The effect of penicillin G, ampicillin and amoxicillin drugs on the corrosion behavior of carbon steel (ASTM 1015) in 1.0 mol L-1 hydrochloric acid solution was investigated using potentiodynamic polarization, electrochemical impedance spectroscopy (EIS) and electrochemical noise (EN) techniques. The inhibition efficiency was found to increase with increasing inhibitor concentration. The effect of temperature on the rate of corrosion in the absence and presence of these drugs was also studied. Some thermodynamic parameters were computed from the effect of temperature on corrosion and inhibition processes. Adsorption of these inhibitors was found to obey Langmuir adsorption isotherm. There was a case of mixed mode of adsorption here but while penicillin was adsorbed mainly through chemisorption, two other drugs were adsorbed mainly through physisorption. Potentiodynamic polarization measurements indicated that the inhibitors were of mixed type. In addition, this paper suggests that the electrochemical noise (EN) technique under open circuit conditions as the truly noninvasive electrochemical method can be employed for the quantitative evaluation of corrosion inhibition. This was done by using the standard deviation of partial signal (SDPS) for calculation of the amount of noise charges at the particular interval of frequency, thereby obtaining the inhibition efficiency (IE) of an inhibitor. These IE values showed a reasonable agreement with those obtained from potentiodynamic polarization and EIS measurements.

  16. Electrochemistry of the antibacterial and antifungal drug nitroxoline and its determination in bulk form, pharmaceutical formulation and human blood.

    PubMed

    Ghoneim, Mohamed M; El-Desoky, Hanaa S; Abdel-Galeil, Mohamed M

    2011-02-01

    Nitroxoline has been reduced at the mercury electrode in buffered solutions (pH 2-11) in two irreversible cathodic steps. The first step was attributed to reduction of -NO(2) group to the hydroxylamine stage and the second one to reduction-saturation of the C=N double bond. DC-polarographic and various adsorptive stripping voltammetric methods were developed for determination of nitroxoline in bulk form. Limits of quantitation of 1.02×10(-6), 3.05×10(-8), 9.01×10(-9), and 9.12×10(-10)M nitroxoline were achieved by means of the developed DC-polarography, differential-pulse-, linear-sweep-, and square-wave-adsorptive cathodic stripping voltammetric methods, respectively. All these electroanalytical methods were successfully applied for determination of nitroxoline in its Nibiol(®) tablets. While only the developed adsorptive stripping voltammetry methods were successfully applied for determination of the drug in spiked human serum and for pharmacokinetic studies in real human plasma. The analysis was carried out without interference from common excipients and without the necessity for prior extraction or interaction with any reagent during the analysis. PMID:20833114

  17. Sequence-motif Detection of NAD(P)-binding Proteins: Discovery of a Unique Antibacterial Drug Target

    NASA Astrophysics Data System (ADS)

    Hua, Yun Hao; Wu, Chih Yuan; Sargsyan, Karen; Lim, Carmay

    2014-09-01

    Many enzymes use nicotinamide adenine dinucleotide or nicotinamide adenine dinucleotide phosphate (NAD(P)) as essential coenzymes. These enzymes often do not share significant sequence identity and cannot be easily detected by sequence homology. Previously, we determined all distinct locally conserved pyrophosphate-binding structures (3d motifs) from NAD(P)-bound protein structures, from which 1d sequence motifs were derived. Here, we aim to establish the precision of these 3d and 1d motifs to annotate NAD(P)-binding proteins. We show that the pyrophosphate-binding 3d motifs are characteristic of NAD(P)-binding proteins, as they are rarely found in nonNAD(P)-binding proteins. Furthermore, several 1d motifs could distinguish between proteins that bind only NAD and those that bind only NADP. They could also distinguish between NAD(P)-binding proteins from nonNAD(P)-binding ones. Interestingly, one of the pyrophosphate-binding 3d and corresponding 1d motifs was found only in enoyl-acyl carrier protein reductases, which are enzymes essential for bacterial fatty acid biosynthesis. This unique 3d motif serves as an attractive novel drug target, as it is conserved across many bacterial species and is not found in human proteins.

  18. In vitro antibacterial activity of some antihistaminics belonging to different groups against multi-drug resistant clinical isolates.

    PubMed

    El-Nakeeb, Moustafa A; Abou-Shleib, Hamida M; Khalil, Amal M; Omar, Hoda G; El-Halfawy, Omar M

    2011-07-01

    Antihistaminics are widely used for various indications during microbial infection. Hence, this paper investigates the antimicrobial activities of 10 antihistaminics belonging to both old and new generations using multiresistant Gram-positive and Gram-negative clinical isolates. The bacteriostatic activity of antihistaminics was investigated by determining their MIC both by broth and agar dilution techniques against 29 bacterial strains. Azelastine, cyproheptadine, mequitazine and promethazine were the most active among the tested drugs. Diphenhydramine and cetirizine possessed weaker activity whereas doxylamine, fexofenadine and loratadine were inactive even at the highest tested concentration (1 mg/ml). The MIC of meclozine could not be determined as it precipitated with the used culture media. The MBC values of antihistaminics were almost identical to the corresponding MIC values. The bactericidal activity of antihistaminics was also studied by the viable count technique in sterile saline solution. Evident killing effects were exerted by mequitazine, meclozine, azelastine and cyproheptadine. Moreover, the dynamics of bactericidal activity of azelastine were studied by the viable count technique in nutrient broth. This activity was found to be concentration-dependant. This effect was reduced on increasing the inoculum size while it was increased on raising the pH. The post-antimicrobial effect of 100 ?g/ml azelastine was also determined and reached up to 3.36 h. PMID:24031715

  19. Sequence-motif Detection of NAD(P)-binding Proteins: Discovery of a Unique Antibacterial Drug Target

    PubMed Central

    Hua, Yun Hao; Wu, Chih Yuan; Sargsyan, Karen; Lim, Carmay

    2014-01-01

    Many enzymes use nicotinamide adenine dinucleotide or nicotinamide adenine dinucleotide phosphate (NAD(P)) as essential coenzymes. These enzymes often do not share significant sequence identity and cannot be easily detected by sequence homology. Previously, we determined all distinct locally conserved pyrophosphate-binding structures (3d motifs) from NAD(P)-bound protein structures, from which 1d sequence motifs were derived. Here, we aim to establish the precision of these 3d and 1d motifs to annotate NAD(P)-binding proteins. We show that the pyrophosphate-binding 3d motifs are characteristic of NAD(P)-binding proteins, as they are rarely found in nonNAD(P)-binding proteins. Furthermore, several 1d motifs could distinguish between proteins that bind only NAD and those that bind only NADP. They could also distinguish between NAD(P)-binding proteins from nonNAD(P)-binding ones. Interestingly, one of the pyrophosphate-binding 3d and corresponding 1d motifs was found only in enoyl-acyl carrier protein reductases, which are enzymes essential for bacterial fatty acid biosynthesis. This unique 3d motif serves as an attractive novel drug target, as it is conserved across many bacterial species and is not found in human proteins. PMID:25253464

  20. Synthesis and anticancer activity of novel curcumin-quinolone hybrids.

    PubMed

    Raghavan, Saiharish; Manogaran, Prasath; Gadepalli Narasimha, Krishna Kumari; Kalpattu Kuppusami, Balasubramanian; Mariyappan, Palanivelu; Gopalakrishnan, Anjana; Venkatraman, Ganesh

    2015-09-01

    A number of new curcumin-quinolone hybrids were synthesised from differently substituted 3-formyl-2-quinolones and vanillin and their in vitro cytotoxicity was determined on a panel of representative cell lines (A549, MCF7, SKOV3 and H460) using MTT assay. The most potent compound 14, was analysed for its mode of action using various cell biology experiments. SKOV3 cells treated with compound 14 showed distorted cell morphology under phase contrast imaging and induction of apoptosis was confirmed by Annexin V/PE assay. Further experiments on generation of reactive oxygen species (ROS) and cell cycle analysis revealed that these hybrids induce apoptosis by ROS generation and arrest cell cycle progression in S and G2/M phase. PMID:26174555

  1. Quinolone resistance and ornithine decarboxylation activity in lactose-negative Escherichia coli

    PubMed Central

    Gomig, Franciane; Galvão, Carolina Weigert; de Freitas, Denis Leandro; Labas, Larissa; Etto, Rafael Mazer; Esmerino, Luiz Antonio; de Lima, Marcelo Andrade; Appel, Marcia Helena; Zanata, Silvio Marques; Steffens, Maria Berenice Reynaud; Nader, Helena Bonciani; da Silveira, Rafael Bertoni

    2015-01-01

    Quinolones and fluoroquinolones are widely used to treat uropathogenic Escherichia coli infections. Bacterial resistance to these antimicrobials primarily involves mutations in gyrA and parC genes. To date, no studies have examined the potential relationship between biochemical characteristics and quinolone resistance in uropathogenic E. coli strains. The present work analyzed the quinolone sensitivity and biochemical activities of fifty-eight lactose-negative uropathogenic E. coli strains. A high percentage of the isolates (48.3%) was found to be resistant to at least one of the tested quinolones, and DNA sequencing revealed quinolone resistant determining region gyrA and parC mutations in the multi-resistant isolates. Statistical analyses suggested that the lack of ornithine decarboxylase (ODC) activity is correlated with quinolone resistance. Despite the low number of isolates examined, this is the first study correlating these characteristics in lactose-negative E. coli isolates. PMID:26413057

  2. New trifluoromethyl quinolone derivatives: synthesis and investigation of antimicrobial properties.

    PubMed

    Panda, Siva S; Jain, Subhash C

    2013-06-01

    A series of quinolone derivatives, containing different heterocyclic amines were prepared. Synthesized compounds were evaluated for their in vitro antimicrobial activities against two Gram-positive bacteria, three Gram-negative bacteria as well as four fungi. All the derivatives showed good activity towards Gram-positive bacteria and less activity towards Gram-negative bacteria. They also showed moderate to comparable activity against Aspergillus niger and Candida albicans and low to moderate antifungal activity against Aspergillus fumigatus and Aspergillus flavus. PMID:23611733

  3. Incidence, epidemiology, and characteristics of quinolone-nonsusceptible Streptococcus pneumoniae in Croatia.

    PubMed

    Pankuch, Glenn A; Bozdogan, Bülent; Nagai, Kensuke; Tambić-Andrasević, Arjana; Schoenwald, Slavko; Tambić, Tera; Kalenić, Smilja; Plesko, Sanja; Tepes, Nastja K; Kotarski, Zdenka; Payerl-Pal, Marina; Appelbaum, Peter C

    2002-08-01

    Among 585 Streptococcus pneumoniae strains isolated in 22 Croatian hospitals 21 strains (3.6%) were quinolone nonsusceptible. MICs of all quinolones were high for seven strains tested with the same serotype (23F) and mutations in gyrA, parC, and parE. The remaining 14 strains were more heterogeneous and had mutations only in parC and/or parE, and the MICs of quinolones were lower for these strains. PMID:12121954

  4. Incidence, Epidemiology, and Characteristics of Quinolone- Nonsusceptible Streptococcus pneumoniae in Croatia

    PubMed Central

    Pankuch, Glenn A.; Bozdogan, Bülent; Nagai, Kensuke; Tambić-Andrašević, Arjana; Schoenwald, Slavko; Tambić, Tera; Kalenić, Smilja; Pleško, Sanja; Tepeš, Nastja K.; Kotarski, Zdenka; Payerl-Pal, Marina; Appelbaum, Peter C.

    2002-01-01

    Among 585 Streptococcus pneumoniae strains isolated in 22 Croatian hospitals 21 strains (3.6%) were quinolone nonsusceptible. MICs of all quinolones were high for seven strains tested with the same serotype (23F) and mutations in gyrA, parC, and parE. The remaining 14 strains were more heterogeneous and had mutations only in parC and/or parE, and the MICs of quinolones were lower for these strains. PMID:12121954

  5. Quinolone and Cephalosporin Resistance in Enteric Fever

    PubMed Central

    Capoor, Malini Rajinder; Nair, Deepthi

    2010-01-01

    Enteric fever is a major public health problem in developing countries. Ciprofloxacin resistance has now become a norm in the Indian subcontinent. Novel molecular substitutions may become frequent in future owing to selective pressures exerted by the irrational use of ciprofloxacin in human and veterinary therapeutics, in a population endemic with nalidixic acid-resistant strains. The therapeutics of ciprofloxacin-resistant enteric fever narrows down to third- and fourth-generation cephalosporins, azithromycin, tigecycline and penems. The first-line antimicrobials ampicillin, chloramphenicol and co-trimoxazole need to be rolled back. Antimicrobial surveillance coupled with molecular analysis of fluoroquinolone resistance is warranted for reconfirming novel and established molecular patterns for therapeutic reappraisal and for novel-drug targets. This review explores the antimicrobial resistance and its molecular mechanisms, as well as novel drugs in the therapy of enteric fever. PMID:20927288

  6. Targeting Integrin-Dependent Adhesion and Signaling with 3-Arylquinoline and 3-Aryl-2-Quinolone Derivatives: A new Class of Integrin Antagonists

    PubMed Central

    Fiorucci, Sandrine; Lin, Xiaochen; Sadoul, Karin; Fournet, Guy; Bouvard, Daniel; Vinogradova, Olga; Joseph, Benoît; Block, Marc R.

    2015-01-01

    We previously reported the anti-migratory function of 3-aryl-2-quinolone derivatives, chemically close to flavonoids (Joseph et al., 2002). Herein we show that 3-arylquinoline or 3-aryl-2-quinolone derivatives disrupt cell adhesion in a dose dependent and reversible manner yet antagonized by artificial integrin activation such as manganese. Relying on this anti-adhesive activity, a Structure-Activity Relationship (SAR) study was established on 20 different compounds to throw the bases of future optimization strategies. Active drugs efficiently inhibit platelet spreading, aggregation, and clot retraction, processes that rely on αllbβ3 integrin activation and clustering. In vitro these derivatives interfere with β3 cytoplasmic tail interaction with kindlin-2 in pulldown assays albeit little effect was observed with pure proteins suggesting that the drugs may block an alternative integrin activation process that may not be directly related to kindlin recruitment. Ex vivo, these drugs blunt integrin signaling assayed using focal adhesion kinase auto-phosphorylation as a read-out. Hence, 3-arylquinoline and 3-aryl-2-quinolone series are a novel class of integrin activation and signaling antagonists. PMID:26509443

  7. Molecular study of quinolone resistance mechanisms and clonal relationship of Salmonella enterica clinical isolates.

    PubMed

    Ballesté-Delpierre, Clara; Solé, Mar; Domènech, Òscar; Borrell, Jordi; Vila, Jordi; Fàbrega, Anna

    2014-02-01

    In the last few years, the number of Salmonella enterica strains resistant to nalidixic acid has steadily increased. In a previous study, the quinolone susceptibility phenotype and genotype of 38 S. enterica clinical isolates (19 S. enterica serovar Typhimurium and 19 S. enterica serovar Enteritidis) were determined. Forty-two percent of the isolates showed nalidixic acid resistance associated with a mutation in gyrA together with putative overexpression of efflux pump(s). In this study, mutations in the quinolone resistance-determining region (QRDR) of parE and the regulators of AcrAB (acrR, marRAB, soxRS and ramR) were analysed. Intracellular accumulation of ciprofloxacin and nalidixic acid was determined. Gene expression of the efflux pump components acrB, tolC, acrF and emrB was also assessed. In addition, an epidemiological study of the isolates by multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) was performed. No mutations were detected in parE, whereas two amino acid substitutions were found in two susceptible strains in MarR (I84L) and AcrR (N214T) in one strain each, although both were suggested to be polymorphisms. No changes in the gene expression of acrB, tolC, acrF and emrB were detected between nalidixic-acid-resistant and -susceptible strains. Intracellular accumulation was not useful to reveal differences. Epidemiological analysis showed an important clonal relatedness among the S. Enteritidis isolates, whereas major divergence was seen for S. Typhimurium. Altogether, these results suggest the presence of previously undiscovered drug efflux pump(s) and confirm the high clonality of S. Enteritidis and the genetic divergence of S. Typhimurium. PMID:24139882

  8. [Antibacterial and anti-algal activity if two traditional drugs in the treatment of urinary tract infection and cystitis in Mali].

    PubMed

    Rokia, Sanogo; Drissa, Diallo; Seydou, Diarra; Colette, Ekoumou; Flabou, Bougoudogo

    2006-01-01

    For the treatment of the urinary infections and the cystitis, the medicinal plants constitute a source of new molecules with an antimicrobial activity and economically accessible to face the apparition of a phenomena of germ resistance to antibiotics. The urinary infections and the cystitis are very spilled and constitute a problem of public health in developing countries. About 50% of women develop a symptomatic urinary tract infection at least once in their life. The urinary infection is, by order of frequency, the first of the non epidemic infectious illnesses. The objective of our survey is to find in Malian Pharmacopoeia, plants with antibacterial and analgesic properties. Five remedies and their plants used in traditional medicine for the treatment of the urinary tract infections and the cystitis have been selected on the basis of ethnobotanic investigations results. Extracts of five remedies and their plants have been tested for their antibacterial activity on the germs responsible for the urinary infections and the cystitis. Extracts containing Stylosanthes erecta P. Beauv (Fabaceae) demonstrated an antibacterial activity against clinical strains of Escherichia coli, responsible of 75 to 80% of the urinary infections. The same extracts demonstrated an analgesic activity against the pain induced by the acetic acid in mice. The antibacterial and analgesic properties can be of great benefit in the treatment of the urinary tract infections and the cystitis. PMID:17390524

  9. In vitro susceptibility of quinolone-resistant Enterobacteriaceae uropathogens to fosfomycin trometamol, in Dakar, Senegal.

    PubMed

    Nabeth, Pierre; Perrier-Gros-Claude, Jean-David; Juergens-Behr, Ann; Dromigny, Jacques-Albert

    2005-01-01

    We conducted a study in order to confirm the eligibility of fosfomycin trometamol as an alternative treatment to quinolones for urinary tract infections. Among 102 quinolone-resistant Enterobacteriaceae strains, resistance rates to first line-prescribed antibiotics were above 77%. The resistance rate to fosfomycin was 2%. PMID:16012011

  10. NATURAL FUNGICIDES FROM RUTA GRAVEOLENS L. LEAVES, INCLUDING A NEW QUINOLONE ALKALOID

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bioassay-directed isolation of antifungal compounds from Ruta graveolens leaves yielded seven compounds (two furanocoumarins, four quinolone alkaloids, including one novel compound (1-methyl-2- 4-[3,4-(methylenedioxy)phenyl]hexyl]-4-quinolone), and one quinoline alkaloid). We also report the 1H and ...

  11. Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)

    PubMed Central

    2012-01-01

    A program was undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a dehydrogenase of the mitochondrial electron transport chain of the malaria parasite Plasmodium falciparum. PfNDH2 has only one known inhibitor, hydroxy-2-dodecyl-4-(1H)-quinolone (HDQ), and this was used along with a range of chemoinformatics methods in the rational selection of 17 000 compounds for high-throughput screening. Twelve distinct chemotypes were identified and briefly examined leading to the selection of the quinolone core as the key target for structure–activity relationship (SAR) development. Extensive structural exploration led to the selection of 2-bisaryl 3-methyl quinolones as a series for further biological evaluation. The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) has antimalarial activity against the 3D7 strain of P. falciparum of 36 nM, is selective for PfNDH2 over other respiratory enzymes (inhibitory IC50 against PfNDH2 of 16 nM), and demonstrates low cytotoxicity and high metabolic stability in the presence of human liver microsomes. This lead compound and its phosphate pro-drug have potent in vivo antimalarial activity after oral administration, consistent with the target product profile of a drug for the treatment of uncomplicated malaria. Other quinolones presented (e.g., 6d, 6f, 14e) have the capacity to inhibit both PfNDH2 and P. falciparum cytochrome bc1, and studies to determine the potential advantage of this dual-targeting effect are in progress. PMID:22364416

  12. Structural signature of Ser83Leu and Asp87Asn mutations in DNA gyrase from enterotoxigenic Escherichia coli and impact on quinolone resistance.

    PubMed

    Mehla, Kusum; Ramana, Jayashree

    2016-01-15

    Enterotoxigenic Escherichia coli (ETEC) is among the most frequent microorganisms causing traveler's diarrhea (TD). Quinolones are potent antimicrobial agents used for the treatment of TD. Resistance to quinolones is typically caused by substitutions in QRDR region of gyrA subunit of DNA gyrase. The aim of this study was to seek insights into the effect of these substitutions at structural level and their association with observed quinolone resistance. Majority of the ETEC strains have gyrA mutations at amino acid position 83 and 87. To understand the quinolone resistance mechanism at molecular level, we have studied the interaction of wild type and mutant forms of ETEC gyrA with nalidixic acid and ciprofloxacin by molecular modeling using Discovery Studio and LeadIt. All the mutants had reduced affinity towards both ciprofloxacin and nalidixic acid relative to the wild type due to the mutations introduced in gyrA. Besides Ser83 and Asp87, for nalidixic acid binding Arg91 and His45 residues were observed to be critical while in ciprofloxacin binding Lys42 and Arg91 residues played a significant role. Amino acid substitutions contribute to the emergence of drug resistance in sensitive strains by causing structural alterations leading to reduced affinity of the drug towards receptor. Analysis of the effect of amino acid substitutions at structural level is of utmost importance to establish possible associations between mutations and the diseases. These studies accelerate the identification of pharmaceutical targets for relevant treatments and could also be helpful in guiding the design of further experimental research. PMID:26424597

  13. In vitro study of cytotoxicity of quinolones on rabbit tenocytes.

    PubMed

    Bernard-Beaubois, K; Hecquet, C; Hayem, G; Rat, P; Adolphe, M

    1998-08-01

    Tendinitis and tendon rupture complicating fluoroquinolone therapy have been reported recently, especially affecting men over 60 years. These new quinolones are more potent antimicrobial agents than older nonfluorinated compounds like nalidixic acid. We compared the effects of one quinolone (nalidixic acid) and two fluoroquinolones (norfloxacin and pefloxacin) on cultured rabbit Achilles tendon cells. First, we examined their effects on cell viability, mitochondrial succinate dehydrogenase and global activity, mitochondrial activity using microtitration methods. Pefloxacin and norfloxacin were more cytotoxic than nalidixic acid according to IC50 values. These results confirm that mitochondria represent a biological target of fluoroquinolones. Moreover, the extracellular matrix was studied by molecular hybridization. After a 72 h treatment, the level of type I collagen transcripts was not modified with any of the three antimicrobial agents, whereas mRNA encoding decorin was decreased with 10(-4) mol/L pefloxacin only. The decrease of transcripts encoding decorin suggests that this matrix component is another target of pefloxacin and modification of decorin seems to be an early event (before mitochondrion alteration) which may contribute to the explanation of tendon rupture. PMID:9733283

  14. Targeting virulence not viability in the search for future antibacterials

    PubMed Central

    Heras, Begoña; Scanlon, Martin J; Martin, Jennifer L

    2015-01-01

    New antibacterials need new approaches to overcome the problem of rapid antibiotic resistance. Here we review the development of potential new antibacterial drugs that do not kill bacteria or inhibit their growth, but combat disease instead by targeting bacterial virulence. PMID:24552512

  15. Synthesis of halogenated 4-quinolones and evaluation of their antiplasmodial activity.

    PubMed

    Vandekerckhove, Stéphanie; Desmet, Tom; Tran, Hai Giang; de Kock, Carmen; Smith, Peter J; Chibale, Kelly; D'hooghe, Matthias

    2014-02-15

    Treatment of 4-hydroxyquinolines with (2-methyl)allyl bromide in the presence of K2CO3 resulted in the formation of novel N-[(2-methyl)allyl]-4-quinolones through selective N-alkylation. Further reaction of N-(2-methylallyl)-4-quinolones with bromine or N-bromosuccinimide yielded the corresponding 3-bromo-1-(2,3-dibromo-2-methylpropyl)-4-quinolones and 3-bromo-1-(2-methylallyl)-4-quinolones, respectively. Furthermore, a copper-catalyzed C-N coupling of the latter 3-bromo-4-quinolones with (5-chloro)indole afforded novel 3-[(5-chloro)indol-1-yl]-4-quinolone hybrids. Antifungal and antiplasmodial assays of all new 4-quinolones were performed and revealed no antifungal properties but moderate antiplasmodial activities. All 15 compounds displayed micromolar activities against a chloroquine-sensitive strain of Plasmodium falciparum, and the five most potent compounds also showed micromolar activities against a chloroquine-resistant strain of P. falciparum with IC50-values ranging between 4 and 70 μM. PMID:24468411

  16. 4(1H)-Pyridone and 4(1H)-Quinolone Derivatives as Antimalarials with Erythrocytic, Exoerythrocytic, and Transmission Blocking Activities

    PubMed Central

    Monastyrskyi, Andrii; Kyle, Dennis E.; Manetsch, Roman

    2015-01-01

    Infectious diseases are the second leading cause of deaths in the world with malaria being responsible for approximately the same amount of deaths as cancer in 2012. Despite the success in malaria prevention and control measures decreasing the disease mortality rate by 45% since 2000, the development of single-dose therapeutics with radical cure potential is required to completely eradicate this deadly condition. Targeting multiple stages of the malaria parasite is becoming a primary requirement for new candidates in antimalarial drug discovery and development. Recently, 4(1H)-pyridone, 4(1H)-quinolone, 1,2,3,4-tetrahydroacridone, and phenoxyethoxy-4(1H)-quinolone chemotypes have been shown to be antimalarials with blood stage activity, liver stage activity, and transmission blocking activity. Advancements in structure-activity relationship and structure-property relationship studies, biological evaluation in vitro and in vivo, as well as pharmacokinetics of the 4(1H)-pyridone and 4(1H)-quinolone chemotypes will be discussed. PMID:25116582

  17. Synthesis and antibacterial evaluation of novel 4″-glycyl linked quinolyl-azithromycins with potent activity against macrolide-resistant pathogens.

    PubMed

    Pavlović, Dražen; Mutak, Stjepan

    2016-03-15

    A new azithromycin-based series of antibacterial macrolones is reported, which features the use of a 4″-ester linked glycin for tethering the quinolone side chain to the macrolide scaffold. Among the analogs prepared, compounds 9e and 22f with a quinolon-6-yl moiety were found to have potent and well-balanced activity against clinically important respiratory tract pathogens, including erythromycin-susceptible and MLSB resistant strains of Streptococcus pneumoniae, Streptococcus pyogenes, and Haemophilus influenzae. In addition, potential lead compounds 9e and 22f demonstrated outstanding levels of activity against Moraxella catarrhalis and inducibly MLSB resistant Staphylococcus aureus. The best member of this series 22f rivals or exceeds, in potency, some of the most active ketolide antibacterial agents known today, such as telithromycin and cethromycin. PMID:26860929

  18. Vitiquinolone--a quinolone alkaloid from Hibiscus vitifolius Linn.

    PubMed

    Ramasamy, D; Saraswathy, A

    2014-02-15

    Phytochemical investigations of the powdered root of Hibiscus vitifolius Linn. (Malvaceae) was extracted successively with n-hexane and chloroform. Analysis of the n-hexane extract by GC-MS led to the identification of twenty-six components by comparison of their mass spectra with GC-MS library data. A novel quinolone alkaloid, vitiquinolone (5) together with eight known compounds viz. β-Amyrin acetate (1), n-octacosanol (2), β-Amyrin (3), stigmasterol (4), xanthyletin (6), alloxanthoxyletin (7), xanthoxyletin (8) and betulinic acid (9) were isolated from chloroform extract by column chromatography over silica gel. The structure of vitiquinolone was established on the basis of spectroscopic methods including UV, IR, 1D, 2D NMR and ESI-MS. The known compounds were identified on the basis of their physical and spectroscopic data as reported in the literature. PMID:24128571

  19. Regulation of Pseudomonas quinolone signal synthesis in Pseudomonas aeruginosa.

    PubMed

    Wade, Dana S; Calfee, M Worth; Rocha, Edson R; Ling, Elizabeth A; Engstrom, Elana; Coleman, James P; Pesci, Everett C

    2005-07-01

    Pseudomonas aeruginosa is an opportunistic pathogen that causes chronic lung infections in cystic fibrosis patients and is a major source of nosocomial infections. This bacterium controls many virulence factors by using two quorum-sensing systems, las and rhl. The las system is composed of the LasR regulator protein and its cell-to-cell signal, N-(3-oxododecanoyl) homoserine lactone, and the rhl system is composed of RhlR and the signal N-butyryl homoserine lactone. A third intercellular signal, the Pseudomonas quinolone signal (PQS; 2-heptyl-3-hydroxy-4-quinolone), also regulates numerous virulence factors. PQS synthesis requires the expression of multiple operons, one of which is pqsABCDE. Previous experiments showed that the transcription of this operon, and therefore PQS production, is negatively regulated by the rhl quorum-sensing system and positively regulated by the las quorum-sensing system and PqsR (also known as MvfR), a LysR-type transcriptional regulator protein. With the use of DNA mobility shift assays and beta-galactosidase reporter fusions, we have studied the regulation of pqsR and its relationship to pqsA, lasR, and rhlR. We show that PqsR binds the promoter of pqsA and that this binding increases dramatically in the presence of PQS, implying that PQS acts as a coinducer for PqsR. We have also mapped the transcriptional start site for pqsR and found that the transcription of pqsR is positively regulated by lasR and negatively regulated by rhlR. These results suggest that a regulatory chain occurs where pqsR is under the control of LasR and RhlR and where PqsR in turn controls pqsABCDE, which is required for the production of PQS. PMID:15968046

  20. Synthesis, Characterization, and Antibacterial Activities of Novel Sulfonamides Derived through Condensation of Amino Group Containing Drugs, Amino Acids, and Their Analogs

    PubMed Central

    Abdul Qadir, Muhammad; Ahmed, Mahmood; Iqbal, Muhammad

    2015-01-01

    Novel sulfonamides were developed and structures of the new products were confirmed by elemental and spectral analysis (FT-IR, ESI-MS, 1HNMR, and 13CNMR). In vitro, developed compounds were screened for their antibacterial activities against medically important gram (+) and gram (−) bacterial strains, namely, S. aureus, B. subtilis, E. coli, and K. pneumoniae. The antibacterial activities have been determined by measuring MIC values (μg/mL) and zone of inhibitions (mm). Among the tested compounds, it was found that compounds 5a and 9a have most potent activity against E. coli with zone of inhibition: 31 ± 0.12 mm (MIC: 7.81 μg/mL) and 30 ± 0.12 mm (MIC: 7.81 μg/mL), respectively, nearly as active as ciprofloxacin (zone of inhibition: 32 ± 0.12 mm). In contrast, all the compounds were totally inactive against the gram (+) B. subtilis. PMID:25802872

  1. DNA topoisomerases from pathogenic fungi: targets for the discovery of antifungal drugs.

    PubMed Central

    Shen, L L; Baranowski, J; Fostel, J; Montgomery, D A; Lartey, P A

    1992-01-01

    DNA topoisomerases, a class of enzymes that change the topological structure of DNA, have been shown to be the target of many therapeutic agents, including antibacterial agents (quinolones) and anticancer agents. These drugs inhibit the enzyme in a unique way so that the enzyme is converted into a cellular poison. Candida albicans and Aspergillus niger are two major opportunistic fungal pathogens. Our results show that these fungi have high levels of both type I and type II topoisomerases (with a minimum of 5 x 10(5) ATP-independent relaxation units and 2 x 10(5) P-4 unknotting units per liter of wild-type C. albicans). The ATP-dependent type II topoisomerase (termed C. albicans topoisomerase II) was purified by approximately 2,000-fold from C. albicans cells by using a simple isolation scheme that consists of three column procedures: hydroxylapatite, phosphocellulose, and heparin-agarose chromatographies. The responses of the Candida and the calf thymus topoisomerase II to some known topoisomerase II inhibitors were measured. Etoposide and 4'-(9-acridinylamino)methanesulfon-m-anisidide, compounds known to inhibit catalysis and to enhance DNA breakage by mammalian topoisomerase II, and A-80198, an etoposide derivative, enhanced cleavage by both enzymes at similar concentrations of these compounds, with the response of the calf thymus topoisomerase II from slightly to fourfold higher in magnitude than the response of the Candida enzyme in the same concentration range. In contrast, A-75272 (a cytotoxic tricyclic quinolone) shows a slightly stronger DNA cleavage enhancement effect with the Candida enzyme than with the mammalian counterpart. The abundance of the enzyme in cells and the different drug responses of the host enzyme and the fungal enzyme suggest that the fungal topoisomerase may serve as a target for the discovery of effective and safe antifungal agents. Images PMID:1336349

  2. Plasmid-mediated quinolone resistance--current knowledge and future perspectives.

    PubMed

    Guan, Xizhou; Xue, Xinying; Liu, Yuxia; Wang, Jing; Wang, Yong; Wang, Jianxin; Wang, Kaifei; Jiang, Hong; Zhang, Lina; Yang, Bing; Wang, N; Pan, Lei

    2013-02-01

    Quinolones are a group of antimicrobial agents that were serendipitously discovered as byproducts of the synthesis of chloroquine. Chemical modifications, such as the addition of fluorine or piperazine, resulted in the synthesis of third- and fourth-generation fluoroquinolones, with broad-spectrum antimicrobial actions against aerobic or anaerobic, Gram-positive or Gram-negative bacteria. The efficacy and consequent widespread use of quinolones and fluoroquinolones has led to a steady global increase in resistance, mediated via gene mutations, alterations in efflux or cell membranes and plasmid-conferred resistance. The first plasmid-mediated quinolone resistance gene, qnrA1, was detected in 1998. Since then, many other genes have been identified and the underlying mechanisms of resistance have been elucidated. This review provides an overview of quinolone resistance, with particular emphasis on plasmid-mediated resistance. PMID:23569126

  3. Occurrence of (fluoro)quinolones and (fluoro)quinolone resistance in soil receiving swine manure for 11 years.

    PubMed

    Xu, Yonggang; Yu, Wantai; Ma, Qiang; Zhou, Hua

    2015-10-15

    Because of the widespread use of antibiotics in animal breeding, the agricultural application of animal manure can lead to the introduction of antibiotics, antibiotic-resistant bacteria and antibiotic resistance genes to the soil and surrounding environment, which may pose a threat to public health. In this study, we investigated the status of (fluoro)quinolone (FQ) residues and FQ resistance levels in soil with and without receiving long-term swine manure. Six FQs (pipemidic acid, lomefloxacin, enrofloxacin, norfloxacin, ciprofloxacin, and ofloxacin) were only detected in manured soil, with individual concentrations ranging from below the detection limit to 27.2 μg kg(-1) and increasing with the increase in swine manure application rates. Higher load rates of swine manure yielded a higher number of ciprofloxacin-resistant (CIPr) bacteria after spreading. A total of 24 CIPr bacterial isolates were obtained from the tested soil, which belonged to four phyla (Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes) or were related to nine different genera. Only 18 isolates from manured soil were positive for five plasmid-mediated quinolone resistance (PMQR) genes (aac(6')-Ib-cr, qnrD, qepA, oqxA, and oqxB). To our knowledge, this study is the first to examine the occurrence of PMQR genes in FQ-resistant bacteria from the soil environment. A similar result was observed for the total DNA from soil, with the exception of aac(6')-Ib being detected in the control sample. The absolute and relative abundances of total PMQR genes also increased with fertilization quantity. Significant correlations were observed between FQ resistance levels and FQ concentrations. These results indicated that the agricultural application of swine manure led to FQ residues and enhanced FQ resistance. This investigation provides baseline data on FQ resistance profiles in soils receiving long-term swine manure. PMID:26042895

  4. Comparative antimycobacterial activities of the newly synthesized quinolone AM-1155, sparfloxacin, and ofloxacin.

    PubMed Central

    Tomioka, H; Saito, H; Sato, K

    1993-01-01

    AM-1155 is a newly synthesized 6-fluoro-8-methoxy quinolone. We assessed its in vitro antimycobacterial activity using sparfloxacin (SPFX) and ofloxacin (OFLX) as comparison drugs. The MICs of these agents for various mycobacterial strains were determined by the agar dilution method with 7H11 medium. AM-1155 had lower MICs for 50 and 90% of tested strains of Mycobacterium kansasii, M. marinum, and M. fortuitum-M. chelonae complex than SPFX and OFLX, and the values for M. tuberculosis, M. scrofulaceum, and the M. avium-M. intracellulare complex were similar to those of SPFX and considerably lower than those of OFLX. In addition, the antimicrobial activity of AM-1155 against M. tuberculosis and M. intracellulare phagocytosed into murine peritoneal macrophages was compared with that of OFLX. AM-1155 (1 microgram/ml) inhibited the intracellular growth of both M. tuberculosis and M. intracellulare, whereas OFLX at the same concentration failed to show any such effect. Moreover, AM-1155 (10 micrograms/ml) exhibited a steady bactericidal action against M. tuberculosis, whereas OFLX at the same concentration had only a weak effect. AM-1155 (10 micrograms/ml) also inhibited the growth of M. intracellulare more effectively than OFLX. PMID:8392307

  5. Cystobactamids: myxobacterial topoisomerase inhibitors exhibiting potent antibacterial activity.

    PubMed

    Baumann, Sascha; Herrmann, Jennifer; Raju, Ritesh; Steinmetz, Heinrich; Mohr, Kathrin I; Httel, Stephan; Harmrolfs, Kirsten; Stadler, Marc; Mller, Rolf

    2014-12-22

    The development of new antibiotics faces a severe crisis inter?alia owing to a lack of innovative chemical scaffolds with activities against Gram-negative and multiresistant pathogens. Herein, we report highly potent novel antibacterial compounds, the myxobacteria-derived cystobactamids 1-3, which were isolated from Cystobacter sp. and show minimum inhibitory concentrations in the low ?g?mL(-1) range. We describe the isolation and structure elucidation of three congeners as well as the identification and annotation of their biosynthetic gene cluster. By studying the self-resistance mechanism in the natural producer organism, the molecular targets were identified as bacterial type?IIa topoisomerases. As quinolones are largely exhausted as a template for new type II topoisomerase inhibitors, the cystobactamids offer exciting alternatives to generate novel antibiotics using medicinal chemistry and biosynthetic engineering. PMID:25510965

  6. Interplay between intrinsic and acquired resistance to quinolones in Stenotrophomonas maltophilia.

    PubMed

    García-León, Guillermo; Salgado, Fabiola; Oliveros, Juan Carlos; Sánchez, María Blanca; Martínez, José Luis

    2014-05-01

    To analyse whether the mutation-driven resistance-acquisition potential of a given bacterium might be a function of its intrinsic resistome, quinolones were used as selective agents and Stenotrophomonas maltophilia was chosen as a bacterial model. S. maltophilia has two elements - SmQnr and SmeDEF - that are important in intrinsic resistance to quinolones. Using a battery of mutants in which either or both of these elements had been removed, the apparent mutation frequency for quinolone resistance and the phenotype of the selected mutants were found to be related to the intrinsic resistome and also depended on the concentration of the selector. Most mutants had phenotypes compatible with the overexpression of multidrug efflux pump(s); SmeDEF overexpression was the most common cause of quinolone resistance. Whole genome sequencing showed that mutations of the SmeRv regulator, which result in the overexpression of the efflux pump SmeVWX, are the cause of quinolone resistance in mutants not overexpressing SmeDEF. These results indicate that the development of mutation-driven antibiotic resistance is highly dependent on the intrinsic resistome, which, at least for synthetic antibiotics such as quinolones, did not develop as a response to the presence of antibiotics in the natural ecosystems in which S. maltophilia evolved. PMID:24447641

  7. Antigiardial activity of novel triazolyl-quinolone-based chalcone derivatives: when oxygen makes the difference

    PubMed Central

    Bahadur, Vijay; Mastronicola, Daniela; Singh, Amit K.; Tiwari, Hemandra K.; Pucillo, Leopoldo P.; Sarti, Paolo; Singh, Brajendra K.; Giuffrè, Alessandro

    2015-01-01

    Giardiasis is a common diarrheal disease worldwide caused by the protozoan parasite Giardia intestinalis. It is urgent to develop novel drugs to treat giardiasis, due to increasing clinical resistance to the gold standard drug metronidazole (MTZ). New potential antiparasitic compounds are usually tested for their killing efficacy against G. intestinalis under anaerobic conditions, in which MTZ is maximally effective. On the other hand, though commonly regarded as an ‘anaerobic pathogen,’ G. intestinalis is exposed to relatively high O2 levels in vivo, living attached to the mucosa of the proximal small intestine. It is thus important to test the effect of O2 when searching for novel potential antigiardial agents, as outlined in a previous study [Bahadur et al. (2014) Antimicrob. Agents Chemother. 58, 543]. Here, 45 novel chalcone derivatives with triazolyl-quinolone scaffold were synthesized, purified, and characterized by high resolution mass spectrometry, 1H and 13C nuclear magnetic resonance and infrared spectroscopy. Efficacy of the compounds against G. intestinalis trophozoites was tested under both anaerobic and microaerobic conditions, and selectivity was assessed in a counter-screen on human epithelial colorectal adenocarcinoma cells. MTZ was used as a positive control in the assays. All the tested compounds proved to be more effective against the parasite in the presence of O2, with the exception of MTZ that was less effective. Under anaerobiosis eighteen compounds were found to be as effective as MTZ or more (up to three to fourfold); the same compounds proved to be up to >100-fold more effective than MTZ under microaerobic conditions. Four of them represent potential candidates for the design of novel antigiardial drugs, being highly selective against Giardia trophozoites. This study further underlines the importance of taking O2 into account when testing novel potential antigiardial compounds. PMID:25904901

  8. Discovery of membrane active benzimidazole quinolones-based topoisomerase inhibitors as potential DNA-binding antimicrobial agents.

    PubMed

    Zhang, Ling; Addla, Dinesh; Ponmani, Jeyakkumar; Wang, Ao; Xie, Dan; Wang, Ya-Nan; Zhang, Shao-Lin; Geng, Rong-Xia; Cai, Gui-Xin; Li, Shuo; Zhou, Cheng-He

    2016-03-23

    A series of novel benzimidazole quinolones as potential antimicrobial agents were designed and synthesized. Most of the prepared compounds exhibited good or even stronger antimicrobial activities in comparison with reference drugs. The most potent compound 15m was membrane active and did not trigger the development of resistance in bacteria. It not only inhibited the formation of biofilms but also disrupted the established Staphylococcus aureus and Escherichia coli biofilms. It was able to inhibit the relaxation activity of E. coli topoisomerase IV at 10 μM concentration. Moreover, this compound also showed low toxicity against mammalian cells. Molecular modeling and experimental investigation of compound 15m with DNA suggested that this compound could effectively bind with DNA to form a steady 15m-DNA complex which might further block DNA replication to exert the powerful bioactivities. PMID:26871658

  9. Antibacterial activity of N-benzylsalicylthioamides.

    PubMed

    Petrlíková, E; Waisser, K; Jílek, P; Dufková, I

    2010-09-01

    The in-vitro biological activity of N-benzylsalicylthioamides against 8 bacterial strains was determined by broth microdilution method; results were compared with those obtained with neomycin, penicillin G, ciprofloxacin and penicillin V. The compounds showed moderate to high activity against G(+) bacteria; especially compounds 4, 6, 13, 16-21 and 24 exhibited comparable or higher activity than reference drugs. The antibacterial activity was analyzed by quantitative structure-activity relationship (QSAR). The antibacterial activity increased with lipophilicity, with the presence of halogens and with increasing value of Hammet substituent constant σ. PMID:20941574

  10. Quinolone Resistance in Absence of Selective Pressure: The Experience of a Very Remote Community in the Amazon Forest

    PubMed Central

    Riccobono, Eleonora; Fernandez, Connie; Mantella, Antonia; Magnelli, Donata; Mannini, Dario; Strohmeyer, Marianne; Bartalesi, Filippo; Rodriguez, Hugo; Gotuzzo, Eduardo; Rossolini, Gian Maria

    2012-01-01

    Background Quinolones are potent broad-spectrum bactericidal agents increasingly employed also in resource-limited countries. Resistance to quinolones is an increasing problem, known to be strongly associated with quinolone exposure. We report on the emergence of quinolone resistance in a very remote community in the Amazon forest, where quinolones have never been used and quinolone resistance was absent in 2002. Methods The community exhibited a considerable level of geographical isolation, limited contact with the exterior and minimal antibiotic use (not including quinolones). In December 2009, fecal carriage of antibiotic resistant Escherichia coli was investigated in 120 of the 140 inhabitants, and in 48 animals reared in the community. All fluoroquinolone-resistant isolates were genotyped and characterized for the mechanisms of plasmid- and chromosomal-mediated quinolone resistance. Principal Findings Despite the characteristics of the community remained substantially unchanged during the period 2002–2009, carriage of quinolone-resistant E. coli was found to be common in 2009 both in humans (45% nalidixic acid, 14% ciprofloxacin) and animals (54% nalidixic acid, 23% ciprofloxacin). Ciprofloxacin-resistant isolates of human and animal origin showed multidrug resistance phenotypes, a high level of genetic heterogeneity, and a combination of GyrA (Ser83Leu and Asp87Asn) and ParC (Ser80Ile) substitutions commonly observed in fluoroquinolone-resistant clinical isolates of E. coli. Conclusions Remoteness and absence of antibiotic selective pressure did not protect the community from the remarkable emergence of quinolone resistance in E. coli. Introduction of the resistant strains from antibiotic-exposed settings is the most likely source, while persistence and dissemination in the absence of quinolone exposure is likely mostly related with poor sanitation. Interventions aimed at reducing the spreading of resistant isolates (by improving sanitation and water/food safety) are urgently needed to preserve the efficacy of quinolones in resource-limited countries, as control strategies based only on antibiotic restriction policies are unlikely to succeed in those settings. PMID:22953012

  11. Comparative in vitro activity of lomefloxacin, a difluoro-quinolone.

    PubMed

    Robbins, M J; Baskerville, A J; Sanghrajka, M; Mumtaz, G; Felmingham, D; Ridgway, G L; Grüneberg, R N

    1989-01-01

    Lomefloxacin is a new difluoro-quinolone. In this study, we have determined the in vitro activity of lomefloxacin against a wide range of clinical bacterial isolates and compared it with that of other fluoro-quinolones and some unrelated antimicrobials. Lomefloxacin was very active against Enterobacteriaceae (MIC90, 0.5 micrograms/ml) with activity comparable to that of ofloxacin (MIC90, 0.25 micrograms/ml). Lomefloxacin was moderately active against isolates of Pseudomonas aeruginosa (MIC90, 4 micrograms/ml), and again the activity was comparable to ofloxacin (MIC90, 4 micrograms/ml) but was eightfold less than ciprofloxacin (MIC90, 0.5 micrograms/ml). Lomefloxacin was also active against isolates of Staphylococcus aureus (MIC90, 1 micrograms/ml), irrespective of methicillin susceptibility, and this activity was most comparable to ofloxacin (MIC90, 0.5 micrograms/ml) and ciprofloxacin (MIC90, 0.5 micrograms/ml). Lomefloxacin was fourfold less active than either ofloxacin or ciprofloxacin against isolates of Enterococcus faecalis (MIC90, 8 micrograms/ml) and Streptococcus pneumoniae (MIC90, 8 micrograms/ml). In common with ofloxacin and ciprofloxacin, lomefloxacin was very active against isolates of Neisseria spp. (MIC90, less than or equal to 0.06 micrograms/ml), Haemophilus spp. (MIC90, less than or equal to 0.06 micrograms/ml), Legionella spp. (MIC90, less than or equal to 0.06 micrograms/ml), Vibrio spp. (MIC90, less than or equal to 0.06 micrograms/ml), and Campylobacter jejuni (MIC90, 1 microgram/ml). Lomefloxacin showed poor activity against isolates of Bacteroides spp. (MIC90, 16 micrograms/ml) or Clostridium difficile MIC90, 32 micrograms/ml) and was only moderately active against isolates of Clostridium perfringens (MIC90, 2 micrograms/ml), Peptostreptococcus spp. (MIC90, 4 micrograms/ml), Chlamydia trachomatis (MIC90, 4 micrograms/ml), Mycoplasma hominis (MIC90, 2 micrograms/ml), and Urea-plasma urealyticum (MIC90, 8 micrograms/ml). Lomefloxacin was found to be bactericidal at concentrations generally close to the MIC with greater than 3 log10 reduction in viability of exponentially dividing cultures of Escherichia coli and S. aureus within 5 hr of exposure to concentrations at eight times the MIC. These results indicate a potential clinical role for lomefloxacin in the treatment of genitourinary tract infections caused by Gram-positive and Gram-negative bacteria, respiratory tract infections caused by susceptible organisms, and soft tissue infections caused by S. aureus. PMID:2791500

  12. Cell-Envelope Remodeling as a Determinant of Phenotypic Antibacterial Tolerance in Mycobacterium tuberculosis

    PubMed Central

    2016-01-01

    The mechanisms that lead to phenotypic antibacterial tolerance in bacteria remain poorly understood. We investigate whether changes in NaCl concentration toward physiologically higher values affect antibacterial efficacy against Mycobacterium tuberculosis (Mtb), the causal agent of human tuberculosis. Indeed, multiclass phenotypic antibacterial tolerance is observed during Mtb growth in physiologic saline. This includes changes in sensitivity to ethionamide, ethambutol, d-cycloserine, several aminoglycosides, and quinolones. By employing organism-wide metabolomic and lipidomic approaches combined with phenotypic tests, we identified a time-dependent biphasic adaptive response after exposure of Mtb to physiological levels of NaCl. A first rapid, extensive, and reversible phase was associated with changes in core and amino acid metabolism. In a second phase, Mtb responded with a substantial remodelling of plasma membrane and outer lipid membrane composition. We demonstrate that phenotypic tolerance at physiological concentrations of NaCl is the result of changes in plasma and outer membrane lipid remodeling and not changes in core metabolism. Altogether, these results indicate that physiologic saline-induced antibacterial tolerance is kinetically coupled to cell envelope changes and demonstrate that metabolic changes and growth arrest are not the cause of phenotypic tolerance observed in Mtb exposed to physiologic concentrations of NaCl. Importantly, this work uncovers a role for bacterial cell envelope remodeling in antibacterial tolerance, alongside well-documented allterations in respiration, metabolism, and growth rate. PMID:27231718

  13. Characterization of quinolone resistance in Salmonella enterica serovar Indiana from chickens in China.

    PubMed

    Lu, Yan; Zhao, Hongyu; Liu, Yuqi; Zhou, Xuping; Wang, Jinyuan; Liu, Tiantian; Beier, Ross C; Hou, Xiaolin

    2015-03-01

    The aim of this study was to characterize the quinolone resistance of Salmonella enterica serovar Indiana isolated from chickens in China. A total of 293 Salmonella strains were isolated from chicken farms and slaughterhouses in Shandong province of China, and 130 (44.4%) were characterized as Salmonella enterica Indiana (chicken farms, n=52 strains; slaughter houses, n=78 strains). All isolate serotypes were tested with the Kauffmann-White classification system and examined for susceptibility to the quinolones: nalidixic acid, enrofloxacin, norfloxacin, and ciprofloxacin. The resistance of the Salmonella Indiana strains to nalidixic acid, enrofloxacin, norfloxacin, and ciprofloxacin were 100, 73.1, 71.2, and 82.7%, and 100, 59.0, 79.5, and 80.2%, respectively. Selected quinolone resistant strains were evaluated for mutations in genes (gyrA, gyrB, parC, and marA) by DNA sequencing. The gyrA mutation was found in all isolates, the parC mutation was only found in some isolates, and the gyrB and marA mutations were not observed. Quinolone resistance was evaluated in the representative isolates by screening for the quinolone resistance determinants, qnrA, qnrB, qnrS, qepA, and aac (6 ')-Ib-cr using PCR technology. The quinolone resistance determinants in Salmonella, qnrA, qnrB, qnrS, and qepA were negative by PCR, but aac(6 ')-Ib-cr had high detection rates of 90.4 and 96.2% in chicken farms and slaughterhouses, respectively. Salmonella Indiana containing the gyrA mutation was prevalent in farms and slaughterhouses and possessed a high frequency of the quinolone resistance determinant aac(6 ')-Ib-cr. These bacteria may have originated from the same source. PMID:25701209

  14. Antibacterial activities of multi drug resistant Myroides odoratimimus bacteria isolated from adult flesh flies (Diptera: sarcophagidae) are independent of metallo beta-lactamase gene

    PubMed Central

    Dharne, M.S.; Gupta, A.K.; Rangrez, A.Y.; Ghate, H.V.; Patole, M.S.; Shouche, Y.S.

    2008-01-01

    Flesh flies (Diptera: Sarcophagidae) are well known cause of myiasis and their gut bacteria have never been studied for antimicrobial activity against bacteria. Antimicrobial studies of Myroides spp. are restricted to nosocomial strains. A Gram-negative bacterium, Myroides sp., was isolated from the gut of adult flesh flies (Sarcophaga sp.) and submitted to evaluation of nutritional parameters using Biolog GN, 16S rRNA gene sequencing, susceptibility to various antimicrobials by disc diffusion method and detection of metallo β-lactamase genes (TUS/MUS). The antagonistic effects were tested on Gram-negative and Gram-positive bacteria isolated from human clinical specimens, environmental samples and insect mid gut. Bacterial species included were Aeromonas hydrophila, A. culicicola, Morganella morganii subsp. sibonii, Ochrobactrum anthropi, Weissella confusa, Escherichia coli, Ochrobactrum sp., Serratia sp., Kestersia sp., Ignatzschineria sp., Bacillus sp. The Myroides sp. strain was resistant to penicillin-G, erythromycin, streptomycin, amikacin, kanamycin, gentamycin, ampicillin, trimethoprim and tobramycin. These strain showed antibacterial action against all bacterial strains except W. confusa, Ignatzschineria sp., A. hydrophila and M. morganii subsp. sibonii. The multidrug resistance of the strain was similar to the resistance of clinical isolates, inhibiting growth of bacteria from clinical, environmental and insect gut samples. The metallo β-lactamase (TUS/MUS) genes were absent, and resistance due to these genes was ruled out, indicating involvement of other secretion machinery. PMID:24031236

  15. The evidence for clonal spreading of quinolone resistance with a particular clonal complex of Campylobacter jejuni.

    PubMed

    Kovač, J; Cadež, N; Lušicky, M; Nielsen, E Møller; Ocepek, M; Raspor, P; Možina, S Smole

    2014-12-01

    Campylobacter is the most prevalent cause of bacterial gastroenteritis worldwide and it represents a significant public health risk of increasing severity due to its escalating resistance to clinically important quinolone and macrolide antibiotics. As a zoonotic pathogen Campylobacter is transmitted along the food chain and naturally cycles from environmental waters, feedstuff, animals and food to humans. We determined antibiotic resistance profiles, as well as multilocus sequence types and flaA-SVR types for 52 C. jejuni isolated in Slovenia from human, animal, raw and cured chicken meat and water samples. Twenty-eight different sequence types, arranged in ten clonal complexes, three new allele types and five new sequence types were identified, indicating the relatively high diversity in a small group of strains. The assignment of strains from different sources to the same clonal complexes indicates their transmission along the food supply chain. The most prevalent clonal complex was CC21, which was also the genetic group with 95% of quinolone-resistant strains. Based on the genetic relatedness of these quinolone-resistant strains identified by polymerase chain reaction with a mismatch amplification mutation assay and sequencing of the quinolone resistance-determining region of the gyrA gene, we conclude that the high resistance prevalence observed indicates the local clonal spread of quinolone resistance with CC21. PMID:24534165

  16. Antibacterial kaolinite/urea/chlorhexidine nanocomposites: Experiment and molecular modelling

    NASA Astrophysics Data System (ADS)

    Holešová, Sylva; Valášková, Marta; Hlaváč, Dominik; Madejová, Jana; Samlíková, Magda; Tokarský, Jonáš; Pazdziora, Erich

    2014-06-01

    Clay minerals are commonly used materials in pharmaceutical production both as inorganic carriers or active agents. The purpose of this study is the preparation and characterization of clay/antibacterial drug hybrids which can be further included in drug delivery systems for treatment oral infections. Novel nanocomposites with antibacterial properties were successfully prepared by ion exchange reaction from two types of kaolinite/urea intercalates and chlorhexidine diacetate. Intercalation compounds of kaolinite were prepared by reaction with solid urea in the absence of solvents (dry method) as well as with urea aqueous solution (wet method). The antibacterial activity of two prepared samples against Enterococcus faecalis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa was evaluated by finding the minimum inhibitory concentration (MIC). Antibacterial studies of both samples showed the lowest MIC values (0.01%, w/v) after 1 day against E. faecalis, E. coli and S. aureus. A slightly worse antibacterial activity was observed against P. aeruginosa (MIC 0.12%, w/v) after 1 day. Since samples showed very good antibacterial activity, especially after 1 day of action, this means that these samples can be used as long-acting antibacterial materials. Prepared samples were characterized by X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). The experimental data are supported by results of molecular modelling.

  17. In vitro antibacterial activity of medicinal plant extracts against Escherichia coli strains from human clinical specimens and interactions with antimicrobial drugs.

    PubMed

    Ushimaru, P I; Barbosa, L N; Fernandes, A A H; Di Stasi, L C; Fernandes, A

    2012-01-01

    The biological properties of medicinal plants have been documented worldwide for many centuries. We aimed to evaluate interactions between crude extracts from Psidium guajava, Zingiber officinale, Cymbopogon citratus, Caryophyllus aromaticus, Mikania glomerata and Allium sativum samples and antimicrobial drugs against Escherichia coli strains. The susceptibility test performed was disc diffusion, and crude extracts were diluted (%v/v) into Müller-Hinton agar (MHA) at one quarter of the minimal inhibitory concentration for 90% (MIC(90%)) of E. coli strains found previously. Synergistic interactions were observed between C. citratus and polymyxin, and A. sativum extracts and gentamicin. The crude A. sativum extract was the only one that did not show any antagonism with the antimicrobial drugs. The results thus showed the potential use of these medicinal plants against E. coli strains, although antagonism with antimicrobial drugs is a negative aspect in the combined therapy of infectious diseases caused by E. coli. PMID:22011190

  18. Biotic inactivation of the Pseudomonas aeruginosa quinolone signal molecule.

    PubMed

    Soh, Eliza Ye-Chen; Chhabra, Siri R; Halliday, Nigel; Heeb, Stephan; Müller, Christine; Birmes, Franziska S; Fetzner, Susanne; Cámara, Miguel; Chan, Kok-Gan; Williams, Paul

    2015-11-01

    In Pseudomonas aeruginosa, quorum sensing (QS) regulates the production of secondary metabolites, many of which are antimicrobials that impact on polymicrobial community composition. Consequently, quenching QS modulates the environmental impact of P. aeruginosa. To identify bacteria capable of inactivating the QS signal molecule 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS), a minimal medium containing PQS as the sole carbon source was used to enrich a Malaysian rainforest soil sample. This yielded an Achromobacter xylosoxidans strain (Q19) that inactivated PQS, yielding a new fluorescent compound (I-PQS) confirmed as PQS-derived using deuterated PQS. The I-PQS structure was elucidated using mass spectrometry and nuclear magnetic resonance spectroscopy as 2-heptyl-2-hydroxy-1,2-dihydroquinoline-3,4-dione (HHQD). Achromobacter xylosoxidans Q19 oxidized PQS congeners with alkyl chains ranging from C1 to C5 and also N-methyl PQS, yielding the corresponding 2-hydroxy-1,2-dihydroquinoline-3,4-diones, but was unable to inactivate the PQS precursor HHQ. This indicates that the hydroxyl group at position 3 in PQS is essential and that A. xylosoxidans inactivates PQS via a pathway involving the incorporation of oxygen at C2 of the heterocyclic ring. The conversion of PQS to HHQD also occurred on incubation with 12/17 A. xylosoxidans strains recovered from cystic fibrosis patients, with P. aeruginosa and with Arthrobacter, suggesting that formation of hydroxylated PQS may be a common mechanism of inactivation. PMID:25809238

  19. Discovery, Synthesis, and Optimization of Antimalarial 4(1H)-Quinolone-3-Diarylethers

    PubMed Central

    2014-01-01

    The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4(1H)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC50 values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone. PMID:24720377

  20. [Common features of antibacterial compounds: an analysis of 104 compounds library].

    PubMed

    Veselov, M S; Sergiev, P V; Osterman, I A; Skvortsov, D A; Golovina, A Ya; Andreyanova, E S; Laptev, I G; Pletnev, P I; Evfratov, S A; Marusich, E I; Leonov, S V; Ivanenkov, Ya A; Bogdanov, A A; Dontsova, O A

    2015-01-01

    Antibacterial compounds are one of the essential classes of clinically important drugs. High throughput screening allowed revealing potential antibiotics active towards any molecular target in bacterial cell. We used a library of 9820 organic compounds with highly diversified structures to screen for antibacterial activity. As the result of automated screening, 103 compounds were found to possess antibacterial activity against Escherichia coli. The properties of these compounds were compared with those of initial library. Non-linear Kohonen mapping was used to analyze the differences between non-active molecules from initial library, identified antibacterial hits and compounds with reported antibacterial activity. It was found that identified antibacterial compounds are located in the separated area of chemical space. It can be therefore suggested that these molecules belong to novel classes of antibacterial compounds and could be studied further. PMID:26716754

  1. PqsBC, a Condensing Enzyme in the Biosynthesis of the Pseudomonas aeruginosa Quinolone Signal

    PubMed Central

    Drees, Steffen Lorenz; Li, Chan; Prasetya, Fajar; Saleem, Muhammad; Dreveny, Ingrid; Williams, Paul; Hennecke, Ulrich; Emsley, Jonas; Fetzner, Susanne

    2016-01-01

    Pseudomonas aeruginosa produces a number of alkylquinolone-type secondary metabolites best known for their antimicrobial effects and involvement in cell-cell communication. In the alkylquinolone biosynthetic pathway, the β-ketoacyl-(acyl carrier protein) synthase III (FabH)-like enzyme PqsBC catalyzes the condensation of octanoyl-coenzyme A and 2-aminobenzoylacetate (2-ABA) to form the signal molecule 2-heptyl-4(1H)-quinolone. PqsBC, a potential drug target, is unique for its heterodimeric arrangement and an active site different from that of canonical FabH-like enzymes. Considering the sequence dissimilarity between the subunits, a key question was how the two subunits are organized with respect to the active site. In this study, the PqsBC structure was determined to a 2 Å resolution, revealing that PqsB and PqsC have a pseudo-2-fold symmetry that unexpectedly mimics the FabH homodimer. PqsC has an active site composed of Cys-129 and His-269, and the surrounding active site cleft is hydrophobic in character and approximately twice the volume of related FabH enzymes that may be a requirement to accommodate the aromatic substrate 2-ABA. From physiological and kinetic studies, we identified 2-aminoacetophenone as a pathway-inherent competitive inhibitor of PqsBC, whose fluorescence properties could be used for in vitro binding studies. In a time-resolved setup, we demonstrated that the catalytic histidine is not involved in acyl-enzyme formation, but contributes to an acylation-dependent increase in affinity for the second substrate 2-ABA. Introduction of Asn into the PqsC active site led to significant activity toward the desamino substrate analog benzoylacetate, suggesting that the substrate 2-ABA itself supplies the asparagine-equivalent amino function that assists in catalysis. PMID:26811339

  2. Phenotypic and molecular characterization of quinolone resistance in Mycobacterium abscessus subsp. bolletii recovered from postsurgical infections.

    PubMed

    de Moura, Vinicius Calado Nogueira; da Silva, Marlei Gomes; Gomes, Karen Machado; Coelho, Fábrice Santana; Sampaio, Jorge Luiz Mello; Mello, Fernanda Carvalho de Queiroz; Lourenço, Maria Cristina da Silva; Amorim, Efigênia de Lourdes Teixeira; Duarte, Rafael Silva

    2012-01-01

    Several outbreaks of infections caused by rapidly growing mycobacteria (RGM) were reported in many Brazilian states (2032 notified cases) from 2004 to 2010. Most of the confirmed cases were mainly associated with Mycobacterium massiliense (recently renamed as Mycobacterium abscessus subsp. bolletii) BRA100 clone, recovered from patients who had undergone invasive procedures in which medical instruments had not been properly sterilized and/or disinfected. Since quinolones have been an option for the treatment of general RGM infections and have been suggested for therapeutic schemes for these outbreaks, we evaluated the in vitro activities of all generations of quinolones for clinical and reference RGM by broth microdilution, and analysed the peptide sequences of the quinolone resistance determining regions (QRDRs) of GyrA and GyrB after DNA sequencing followed by amino acid translation. Fifty-four isolates of M. abscessus subsp. bolletii, including clone BRA100, recovered in different states of Brazil, and 19 reference strains of RGM species were characterized. All 54 M. abscessus subsp. bolletii isolates were resistant to all generations of quinolones and showed the same amino acids in the QRDRs, including the Ala-83 in GyrA, and Arg-447 and Asp-464 in GyrB, described as being responsible for an intrinsic low level of resistance to quinolones in mycobacteria. However, other RGM species showed distinct susceptibilities to this class of antimicrobials and patterns of mutations contrary to what has been traditionally defined, suggesting that other mechanisms of resistance, different from gyrA or gyrB mutations, may also be involved in resistance to high levels of quinolones. PMID:21903825

  3. Macrolides vs. quinolones for community-acquired pneumonia: meta-analysis of randomized controlled trials.

    PubMed

    Skalsky, K; Yahav, D; Lador, A; Eliakim-Raz, N; Leibovici, L; Paul, M

    2013-04-01

    The relative efficacy, safety and ecological implications of macrolides vs. quinolones in the treatment of community-acquired pneumonia (CAP) are debatable. We performed a systematic review and meta-analysis of randomized controlled trials comparing any macrolide vs. any quinolone for the treatment of CAP among adult inpatients or outpatients, as monotherapy or both in combination with a beta-lactam. We did not limit inclusion by pneumonia severity, publication status, language or date of publication. The primary outcomes assessed were 30-day all-cause mortality and treatment failure. Two authors independently extracted the data. Fixed effect meta-analysis of risk ratios (RRs) with 95% confidence intervals was performed. Sixteen trials (4989 patients) fulfilling inclusion criteria were identified, mostly assessing outpatients with mild to moderate CAP. All-cause mortality was not significantly different for macrolides vs. quinolones, RR 1.03 (0.63-1.68, seven trials), with a low event rate (2%). Treatment failure was significantly lower with quinolones, RR 0.78 (0.67-0.91, 16 trials). The definition of failure used in the primary studies was not clearly representative of patients' benefit. Microbiological failure was lower with quinolones, RR 0.63 (0.49-0.81, 13 trials). All adverse events, adverse events requiring discontinuation and any premature antibiotic discontinuation were significantly more frequent with macrolides, mainly on account of gastrointestinal adverse events. Resistance development was not assessed in the trials. Randomized controlled trials show an advantage of quinolones in the treatment of CAP with regard to clinical cure without need for antibiotic modification at end of treatment and gastrointestinal adverse events. The clinical significance of this advantage is unclear. PMID:22489673

  4. Osteomyelitis of the spine due to Salmonella infection — conservative treatment with quinolone: a case report

    PubMed Central

    Tsui, Hon-For; Chiu, Kwok-Hing; Leung, Kwok-Sui

    1997-01-01

    Although osteomyelitis due to Salmonella infection is known to be associated with sickle cell anemia, various hemoglobinopathies and immune suppressive states, it may also occur in normal hosts. A 16-year-old Chinese boy without sickle cell disease or any other condition that would compromise the immune system had osteomyelitis of the lumbar spine caused by Salmonella enteritidis. The condition was treated conservatively with ciprofloxacin (quinolone group). This may be the first reported case in which a patient with spinal osteomyelitis due to Salmonella infection, who was otherwise healthy, was successfully treated nonoperatively with quinolone. PMID:9030084

  5. Synthesis of Azide-Tagged Library of 2,3-Dihydro-4-Quinolones

    PubMed Central

    Lee, Hajoong; Suzuki, Masato; Cui, Jiayue; Kozmin, Sergey A.

    2010-01-01

    We describe the assembly of a 960-member library of tricyclic 2,3-dihydro-4-quinolones using a combination of solution-phase high-throughput organic synthesis and parallel chromatographic purification. The library was produced with high efficiency and complete chemo and diastereoselectivity by diversification of an azide-bearing quinolone via a sequence of [4+2] cycloadditions, N-acylations and reductive aminations. The azide-functionalization of this library is designed to facilitate subsequent preparation of fluorescent or affinity probes, as well as small-molecule/surface conjugation. PMID:20141224

  6. Antimicrobial (Drug) Resistance Prevention

    MedlinePlus

    ... gov . Related Links Antibacterial Resistance Leadership Group (ARLG) Microbiology and Infectious Diseases Resources for Researchers NIAID Antimicrobial ... to properly dispose of unused medications, visit the Food and Drug Administration website . Healthy lifestyle habits, including ...

  7. [Comparison of antimicrobial use density (AUD) of carbapenem antibacterial agents and investigation of the drug susceptibility of Pseudomonas aeruginosa in 3 hospitals in southern Ibaraki Prefecture, Japan].

    PubMed

    Oishi, Tsuyoshi; Hitomi, Shigemi; Kamoshita, Masaharu; Fukue, Hidetaka; Kawahata, Daisuke; Fukutake, Katsuyuki

    2008-07-01

    The optimal use of anti-Pseudomonas agents is an important issue in the prevention of a tolerance against Pseudomonas aeruginosa. We evaluated the effect of antimicrobial use density (AUD) of carbapenem on drug susceptibility. The AUD of the four carbapenems, imipenem (IPM/CS), panipenem (PAPM/BP), meropenem (MEPM), and biapenem (BIPM), was examined at three hospitals in Ibaraki Prefecture, between April and September 2004. The AUD was calculated using the Defined Daily Doses (DDD) methodology developed by the WHO. A drug susceptibility test was conducted on the 306 Pseudomonas aeruginosa strains randomly collected from clinical specimens at the three hospitals between September and December 2004. In accordance with the standards set by the Clinical and Laboratory Standards Institute (CLSI), minimal inhibitory concentration (MIC) was measured using the broth microdilution method. The results showed that the AUD of carbapenem at the three hospitals tended to be higher than that in other research results in Japan. At one of the three hospitals, the AUD of the PAPM was remarkably high compared to the other carbapenems. Furthermore, P. aeruginosa strains collected at this hospital showed a low susceptibility to carbapenem, and many highly tolerant strains were also observed in this hospital. In order to maintain the susceptibility of Pseudomonas aeruginosa to carbapenem, the overall extent of carbapenem use must be optimal. The use of antimicrobial drugs should be controlled properly at each hospital, in order to prevent excessive use of PAPM/BP from being used over a long period of time. PMID:18709988

  8. Escherichia coli resistant to cephalosporins and quinolones is still susceptible to the cephalosporin-quinolone ester Ro 23-9424.

    PubMed Central

    Pace, J; Bertasso, A; Georgopapadakou, N H

    1991-01-01

    Ro 23-9424 is a broad-spectrum antibacterial agent consisting of a cephalosporin (desacetylcefotaxime) linked through an ester bond to a fluoroquinolone (fleroxacin). Its activity against mutants of Escherichia coli TE18 resistant to both antibacterial components was examined. E. coli TE18 overproduces the AmpC beta-lactamase and is resistant to several cephalosporins, including desacetylcefotaxime (MIC, 50 micrograms/ml), although it is still susceptible to Ro 23-9424 (MIC, 0.2 microgram/ml). Thirty-five spontaneous, two-step mutants of E. coli TE18 which were resistant to fleroxacin (MIC, 50 micrograms/ml) were isolated. In the mutants, replicative DNA biosynthesis (permeabilized cells) was resistant to fleroxacin, and some mutants had porin abnormalities. However, all remained susceptible to Ro 23-9424 (MIC, 0.5 microgram/ml). Examination of beta-lactamase activity in the parent strain revealed that it hydrolyzes desacetylcefotaxime more rapidly than it does Ro 23-9424. Thus, Ro 23-9424 may be less susceptible to the gram-negative, chromosomal beta-lactamases that hydrolyze several broad-spectrum cephalosporins and may be effective in cases in which neither of its two components is active. Images PMID:1649574

  9. Natural Product Leads for Drug Discovery: Isolation, Synthesis and Biological Evaluation of 6-Cyano-5-methoxyindolo[2,3-a]carbazole Based Ligands as Antibacterial Agents

    PubMed Central

    Guo, Songpo; Tipparaju, Suresh K.; Pegan, Scott D.; Wan, Baojie; Mo, Shunyan; Orjala, Jimmy; Mesecar, Andrew D.; Franzblau, Scott G.; Kozikowski, Alan P.

    2010-01-01

    Indolo[2,3-a]carbazole based inhibitors were synthesized from readily available indigo via a seven-step linear synthetic sequence with a moderate overall yield. The inhibitors were selectively and readily functionalized at the nitrogen on the indole portion of the carbazole unit. The synthesized analogs displayed moderate inhibitory activities toward B. anthracis and M. tuberculosis, indicating that indolo[2,3-a]carbazoles could serve as promising leads in the development of new drugs to combat anthrax and tuberculosis infections. PMID:19783449

  10. The association of DNA damage response and nucleotide level modulation with the antibacterial mechanism of the anti-folate drug Trimethoprim

    PubMed Central

    2011-01-01

    Background Trimethoprim is a widely prescribed antibiotic for a variety of bacterial infections. It belongs to a class of anti-metabolites - antifolates - which includes drugs used against malarial parasites and in cancer therapy. However, spread of bacterial resistance to the drug has severely hampered its clinical use and has necessitated further investigations into its mechanism of action and treatment regimen. Trimethoprim selectively starves bacterial cells for tetrahydrofolate, a vital cofactor necessary for the synthesis of several metabolites. The outcome (bacteriostatic or bactericidal) of such starvation, however, depends on the availability of folate-dependent metabolites in the growth medium. To characterize this dependency, we investigated in detail the regulatory and structural components of Escherichia coli cellular response to trimethoprim in controlled growth and supplementation conditions. Results We surveyed transcriptional responses to trimethoprim treatment during bacteriostatic and bactericidal conditions and analyzed associated gene sets/pathways. Concurrent starvation of all folate dependent metabolites caused growth arrest, and this was accompanied by induction of general stress and stringent responses. Three gene sets were significantly associated with the bactericidal effect of TMP in different media including LB: genes of the SOS regulon, genes of the pyrimidine nucleotide biosynthetic pathway and members of the multiple antibiotic resistance (mar) regulon controlled by the MarR repressor. However, the SOS response was identified as the only universal transcriptional signature associated with the loss of viability by direct thymine starvation or by folate stress. We also used genome-wide gene knock-out screen to uncover means of sensitization of bacteria to the drug. We observed that among a number of candidate genes and pathways, the effect of knock-outs in the deoxyribose nucleotide salvage pathway, encoded by the deoCABD operon and under the control of the DeoR repressor, was most informative. Conclusion Transcriptional induction of DNA damage response is an essential feature of the bactericidal effect of trimethoprim. Either the observation of the transcriptional response or DNA damage itself, or both, is made possible by thymine starvation when other folate-dependent metabolites are not limited. The effect of DNA damage by the drug takes place prior to its bactericidal effect, at the beginning of the lag stage of the treatment. Mutations in the deoxyribose nucleotide salvage pathway can affect duration of the lag as well as the rate of killing. This information can be used to postulate certain mechanistic differences between direct thymine starvation in thymidylate synthase deficient mutants and thymine starvation by anti-folate inhibitors. PMID:22122981

  11. Antibacterial peptides: basic facts and emerging concepts.

    PubMed

    Boman, H G

    2003-09-01

    Antibacterial peptides are the effector molecules of innate immunity. Generally they contain 15-45 amino acid residues and the net charge is positive. The cecropin type of linear peptides without cysteine were found first in insects, whilst the defensin type with three disulphide bridges were found in rabbit granulocytes. Now a database stores more than 800 sequences of antibacterial peptides and proteins from the animal and plant kingdoms. Generally, each species has 15-40 peptides made from genes, which code for only one precursor. The dominating targets are bacterial membranes and the killing reaction must be faster than the growth rate of the bacteria. Some antibacterial peptides are clearly multifunctional and an attempt to predict this property from the hydrophobicity of all amino acid side chains are given. Gene structures and biosynthesis are known both in the fruit fly Drosophila and several mammals. Humans need two classes of defensins and the cathelicidin-derived linear peptide LL-37. Clinical cases show that deficiencies in these peptides give severe symptoms. Examples given are morbus Kostmann and atopic allergy. Several antibacterial peptides are being developed as drugs. PMID:12930229

  12. Antibacterial constituents of Neohyptis paniculata.

    PubMed

    Rahman, M Mukhlesur; Gibbons, Simon

    2015-09-01

    A new α-pyrone, 6R-[5R,6S-diacetyloxy-1Z,3E-heptadienyl]-5,6-dihydro-2H-pyran-2one (1), along with six known compounds including an α-pyrone, flavones and terpenes was isolated from the aerial parts of Neohyptis paniculata. The structure of 1 was established unambiguously by MS and a series of 1D and 2D-NMR spectroscopic analyses. The antibacterial activity of the compounds (1-7) was investigated against five strains of multi-drug resistant (MDR) and methicillin-resistant Staphylococcus aureus and minimum inhibitory concentrations (MICs) of these compounds were found to be in the range of 64-256 μg/mL. PMID:26208955

  13. Optical control of antibacterial activity

    NASA Astrophysics Data System (ADS)

    Velema, Willem A.; van der Berg, Jan Pieter; Hansen, Mickel J.; Szymanski, Wiktor; Driessen, Arnold J. M.; Feringa, Ben L.

    2013-11-01

    Bacterial resistance is a major problem in the modern world, stemming in part from the build-up of antibiotics in the environment. Novel molecular approaches that enable an externally triggered increase in antibiotic activity with high spatiotemporal resolution and auto-inactivation are highly desirable. Here we report a responsive, broad-spectrum, antibacterial agent that can be temporally activated with light, whereupon it auto-inactivates on the scale of hours. The use of such a ‘smart’ antibiotic might prevent the build-up of active antimicrobial material in the environment. Reversible optical control over active drug concentration enables us to obtain pharmacodynamic information. Precisely localized control of activity is achieved, allowing the growth of bacteria to be confined to defined patterns, which has potential for the development of treatments that avoid interference with the endogenous microbial population in other parts of the organism.

  14. Quinolone therapy of Klebsiella pneumoniae sepsis following irradiation: Comparison of pefloxacin, ciprofloxacin, and ofloxacin

    SciTech Connect

    Brook, I.; Elliott, T.B.; Ledney, G.D. )

    1990-05-01

    Exposure to whole-body irradiation is associated with fatal gram-negative sepsis. The effect of oral therapy with three quinolones, pefloxacin, ciprofloxacin, and ofloxacin, for orally acquired Klebsiella pneumoniae infection was tested in B6D2F1 mice exposed to 8.0 Gy whole-body irradiation from bilaterally positioned 60Co sources. A dose of 10(8) organisms was given orally 2 days after irradiation, and therapy was started 1 day later. Quinolones reduced colonization of the ileum with K. pneumoniae: 16 of 28 (57%) untreated mice harbored the organisms, compared to only 12 of 90 (13%) mice treated with quinolones (P less than 0.005). K. pneumoniae was isolated from the livers of 6 of 28 untreated mice, compared to only 1 of 90 treated mice (P less than 0.001). Only 5 of 20 (25%) untreated mice survived for at least 30 days compared with 17 of 20 (85%) mice treated with ofloxacin, 15 of 20 (75%) mice treated with pefloxacin, and 14 of 20 (70%) treated with ciprofloxacin (P less than 0.05). These data illustrate the efficacy of quinolones for oral therapy of orally acquired K. pneumoniae infection in irradiated hosts.

  15. Use of the quinolones for the prophylaxis and therapy of infections in immunocompromised hosts.

    PubMed

    Maschmeyer, G

    1993-01-01

    The prevention and treatment of infections are major issues of supportive care in patients with haematological malignancies. Because of their broad antimicrobial activity, the use of fluoroquinolones for prophylaxis in neutropenic patients has been extensively studied. In comparison with placebo, norfloxacin reduces the incidence of Gram-negative infections, whereas Gram-positive bacterial and fungal infections remain unaffected. Ofloxacin and enoxacin also bacterial and fungal infections remain unaffected. Ofloxacin and enoxacin also produce a reduction in fever and documented infections. In randomized studies comparing ciprofloxacin with cotrimoxazole (trimethoprim/sulfamethoxazole) plus colistin (each in combination with nonabsorbable antifungal agents), conflicting results were obtained. The incidence of documented Gram-negative bacterial infections was markedly reduced by ciprofloxacin prophylaxis; however, the number of Gram-positive infections may increase dramatically. Combining ciprofloxacin with a macrolide antibiotic in an attempt to prevent streptococcal infections can result in breakthrough bacteraemias due to resistant Gram-positive pathogens. Empirical antimicrobial therapy after quinolone prophylaxis should also be directed against microorganisms susceptible to quinolones, since sustained eradication by oral administration cannot be assumed with certainty. Clinical trials comparing intravenous quinolones in combination with aminoglycosides with widely used standard regimens for the treatment of infections in cancer patients indicate equivalent efficacy; however, in studies of ciprofloxacin alone, response rates were significantly lower compared with standard combinations. Therefore, quinolone monotherapy as empirical treatment in febrile neutropenic patients cannot be recommended. PMID:7689455

  16. Quinine bis-conjugates with quinolone antibiotics and peptides: synthesis and antimalarial bioassay.

    PubMed

    Panda, Siva S; Bajaj, Kiran; Meyers, Marvin J; Sverdrup, Francis M; Katritzky, Alan R

    2012-12-01

    Benzotriazole-mediated syntheses led to novel bis-conjugates of quinine with quinolone antibiotics and amino acid linkers which were successfully prepared by two alternative routes with excellent yields and retention of chirality. These bis conjugates retain in vitro antimalarial activity with IC(50) values ranging from 12 to 207 nM, similar to quinine itself. PMID:23070233

  17. Plasmid-mediated quinolone resistance among non-typhi Salmonella enterica isolates, USA

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We determined the prevalence of plasmid-mediated quinolone resistance mechanisms among non-Typhi Salmonella (NTS) spp. isolates from humans, food animals, and retail meat in the United States in 2007. Fifty-one (2.4%) of human isolates (n=2165), 5 (1.6%) of isolates from animal isolates (n=1915) an...

  18. Antimicrobial Susceptibility and Mechanisms of Resistance to Quinolones and β-Lactams in Acinetobacter Genospecies 3

    PubMed Central

    Ribera, A.; Fernández-Cuenca, F.; Beceiro, A.; Bou, G.; Martínez-Martínez, L.; Pascual, A.; Cisneros, J. M.; Rodríguez-Baño, J.; Pachón, J.; Vila, J.

    2004-01-01

    Antimicrobial susceptibility was determined in 15 epidemiologically unrelated clinical isolates of Acinetobacter genospecies 3. Moreover, the mechanisms of resistance to some β-lactam antibiotics may be associated with the presence of a chromosomal cephalosporinase, AmpC, and the resistance to quinolones related to mutations in the gyrA and parC genes. PMID:15047561

  19. Effects of DU-6859a, a New Quinolone Antimicrobial, on Theophylline Metabolism in In Vitro and In Vivo Studies

    PubMed Central

    Niki, Yoshihito; Itokawa, Kenichi; Okazaki, Osamu

    1998-01-01

    In vitro and in vivo studies were conducted to investigate the drug interaction between a new quinolone antimicrobial, DU-6859a, and theophylline (TP). The effect of DU-6859a on TP metabolism was evaluated in vitro by measuring the rate of TP metabolite formation by using human liver microsomes. DU-6859a inhibited the metabolism of TP, especially the formation of 1-methylxanthine, in vitro, but to a lesser extent than other drugs that are known to interact with TP. TP was administered alone (200 mg twice a day [b.i.d.] for 9 days) or in combination with DU-6859a (50 or 100 mg b.i.d. for 5 days) to six healthy subjects. DU-6859a administered at a dose of 50 mg resulted in no changes in serum TP concentrations, and slight increases in serum TP concentrations were observed at a dose of 100 mg. Moreover, the administration of 100 mg of DU-6859a resulted in decreases in all urinary TP metabolites, with significant differences. It appears that although DU-6859a has a weak inhibitory effect on TP metabolism in vitro, its concomitant use with TP at clinical dosage levels does not cause any adverse effects, showing only a slight increase in blood TP concentrations and a decrease in urinary metabolites. PMID:9661016

  20. The inactivation of RNase G reduces the Stenotrophomonas maltophilia susceptibility to quinolones by triggering the heat shock response.

    PubMed

    Bernardini, Alejandra; Corona, Fernando; Dias, Ricardo; Sánchez, Maria B; Martínez, Jose L

    2015-01-01

    Quinolone resistance is usually due to mutations in the genes encoding bacterial topoisomerases. However, different reports have shown that neither clinical quinolone resistant isolates nor in vitro obtained Stenotrophomonas maltophilia mutants present mutations in such genes. The mechanisms so far described consist on efflux pumps' overexpression. Our objective is to get information on novel mechanisms of S. maltophilia quinolone resistance. For this purpose, a transposon-insertion mutant library was obtained in S. maltophilia D457. One mutant presenting reduced susceptibility to nalidixic acid was selected. Inverse PCR showed that the inactivated gene encodes RNase G. Complementation of the mutant with wild-type RNase G allele restored the susceptibility to quinolones. Transcriptomic and real-time RT-PCR analyses showed that several genes encoding heat-shock response proteins were expressed at higher levels in the RNase defective mutant than in the wild-type strain. In agreement with this situation, heat-shock reduces the S. maltophilia susceptibility to quinolone. We can then conclude that the inactivation of the RNase G reduces the susceptibility of S. maltophilia to quinolones, most likely by regulating the expression of heat-shock response genes. Heat-shock induces a transient phenotype of quinolone resistance in S. maltophilia. PMID:26539164

  1. The inactivation of RNase G reduces the Stenotrophomonas maltophilia susceptibility to quinolones by triggering the heat shock response

    PubMed Central

    Bernardini, Alejandra; Corona, Fernando; Dias, Ricardo; Sánchez, Maria B.; Martínez, Jose L.

    2015-01-01

    Quinolone resistance is usually due to mutations in the genes encoding bacterial topoisomerases. However, different reports have shown that neither clinical quinolone resistant isolates nor in vitro obtained Stenotrophomonas maltophilia mutants present mutations in such genes. The mechanisms so far described consist on efflux pumps’ overexpression. Our objective is to get information on novel mechanisms of S. maltophilia quinolone resistance. For this purpose, a transposon-insertion mutant library was obtained in S. maltophilia D457. One mutant presenting reduced susceptibility to nalidixic acid was selected. Inverse PCR showed that the inactivated gene encodes RNase G. Complementation of the mutant with wild-type RNase G allele restored the susceptibility to quinolones. Transcriptomic and real-time RT-PCR analyses showed that several genes encoding heat-shock response proteins were expressed at higher levels in the RNase defective mutant than in the wild-type strain. In agreement with this situation, heat-shock reduces the S. maltophilia susceptibility to quinolone. We can then conclude that the inactivation of the RNase G reduces the susceptibility of S. maltophilia to quinolones, most likely by regulating the expression of heat-shock response genes. Heat-shock induces a transient phenotype of quinolone resistance in S. maltophilia. PMID:26539164

  2. A series of 2D metal-quinolone complexes: Syntheses, structures, and physical properties

    SciTech Connect

    He, Jiang-Hong; Xiao, Dong-Rong; Chen, Hai-Yan; Sun, Dian-Zhen; Yan, Shi-Wei; Wang, Xin; Ye, Zhong-Li; Luo, Qun-Li; Wang, En-Bo

    2013-02-15

    Six novel 2D metal-quinolone complexes, namely [Cd(cfH)(bpdc)]{center_dot}H{sub 2}O (1), [M(norfH)(bpdc)]{center_dot}H{sub 2}O (M=Cd (2) and Mn (3)), [Mn{sub 2}(cfH)(odpa)(H{sub 2}O){sub 3}]{center_dot}0.5H{sub 2}O (4), [Co{sub 2}(norfH)(bpta)({mu}{sub 2}-H{sub 2}O)(H{sub 2}O){sub 2}]{center_dot}H{sub 2}O (5) and [Co{sub 3}(saraH){sub 2}(Hbpta){sub 2}(H{sub 2}O){sub 4}]{center_dot}9H{sub 2}O (6) (cfH=ciprofloxacin, norfH=norfloxacin, saraH=sarafloxacin, bpdc=4,4 Prime -biphenyldicarboxylate, odpa=4,4 Prime -oxydiphthalate, bpta=3,3 Prime ,4,4 Prime -biphenyltetracarboxylate) have been synthesized and characterized. Compounds 1-3 consist of 2D arm-shaped layers based on the 1D {l_brace}M(COO){r_brace}{sub n}{sup n+} chains. Compounds 4 and 5 display 2D structures based on tetranuclear manganese or cobalt clusters with (3,6)-connected kgd topology. Compound 6 exhibits a 2D bilayer structure, which represents the first example of metal-quinolone complexes with 2D bilayer structure. By inspection of the structures of 1-6, it is believed that the long aromatic polycarboxylate ligands are important for the formation of 2D metal-quinolone complexes. The magnetic properties of compounds 3-6 was studied, indicating the existence of antiferromagnetic interactions. Furthermore, the luminescent properties of compounds 1-2 are discussed. - Graphical abstract: Six novel 2D metal-quinolone complexes have been prepared by self-assemblies of the quinolones and metal salts in the presence of long aromatic polycarboxylates. Highlights: Black-Right-Pointing-Pointer Compounds 1-3 consist of novel 2D arm-shaped layers based on the 1D {l_brace}M(COO){r_brace}{sub n}{sup n+} chains. Black-Right-Pointing-Pointer Compounds 4 and 5 are two novel 2D layers based on tetranuclear Mn or Co clusters with kgd topology. Black-Right-Pointing-Pointer Compound 6 is the first example of metal-quinolone complexes with 2D bilayer structure. Black-Right-Pointing-Pointer Compounds 1-6 represent six unusual examples of 2D metal-quinolone complexes.

  3. Microbial screening for quinolones residues in cow milk by bio-optical method.

    PubMed

    Appicciafuoco, Brunella; Dragone, Roberto; Frazzoli, Chiara; Bolzoni, Giuseppe; Mantovani, Alberto; Ferrini, Anna Maria

    2015-03-15

    The use of antibiotics on lactating cows should be monitored for the possible risk of milk contamination with residues. Accordingly, Maximum Residue Levels (MRLs) are established by the European Commission to guarantee consumers safety. As pointed out by Dec 2002/657/EC, screening is the first step in the strategy for antibiotic residue control, thus playing a key role in the whole control procedure. However, current routine screening methods applied in milk chain still fail to detect residues of quinolones at concentrations of interest. This paper reports the findings of a new bio-optical method for the screening of quinolones residues in bovine milk, based on E. coli ATCC 11303 growth inhibition. The effect of blank and spiked cow milk samples (aliquots equivalents to 0.8%, v/v) is evaluated in Mueller Hinton Broth (MHb) and MHb enriched with MgSO4 2% (MHb-Mg) inoculated with the test strain at the concentration of 10(4)CFU/mL. The presence of quinolones inhibits the cellular growth in MHb, while this effect is neutralized in MHb-Mg allowing both detection and presumptive identification of quinolones. Growth of the test strain is monitored at 37 °C in a Bioscreen C automated system, and Optical Density (OD) at 600 nm is recorded every 10 min after shaking for 10s. Growth curves (OD vs. time) of E. coli ATCC 11303 are assessed in milk samples, with and without quinolones, and their differences in terms of ΔOD (ΔOD600nm=ODMHb-Mg-ODMHb) are calculated. The presence of quinolones is detected by the cellular growth inhibition (OD vs time, none increase in the value OD) and presumptively identified through the increase of the slope of ΔOD600nm curve (ΔOD vs. time), after about 3h of incubation. The detection limit for ciprofloxacin and enrofloxacin is at the level of MRL, for marbofloxacin is at 2-fold the MRL whereas for danofloxacin is at 4-fold the MRL. Although the sensitivity of the method could be further improved and the procedure automated, it is a promising step forward to integrate screening assays into the control process and, in particular, to fill in the gap for quinolones; moreover, these technological developments contribute to the One Health perspective through the monitoring of safe and correct use of veterinary antibiotics. PMID:25555518

  4. Developing Outcomes Assessments as Endpoints for Registrational Clinical Trials of Antibacterial Drugs: 2015 Update From the Biomarkers Consortium of the Foundation for the National Institutes of Health.

    PubMed

    Talbot, George H; Powers, John H; Hoffmann, Steven C

    2016-03-01

    One important component in determining the benefits and harms of medical interventions is the use of well-defined and reliable outcome assessments as endpoints in clinical trials. Improving endpoints can better define patient benefits, allowing more accurate assessment of drug efficacy and more informed benefit-vs-risk decisions; another potential plus is facilitating efficient trial design. Since our first report in 2012, 2 Foundation for the National Institutes of Health Biomarkers Consortium Project Teams have continued to develop outcome assessments for potential uses as endpoints in registrational clinical trials of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. In addition, the teams have initiated similar work in the indications of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. This report provides an update on progress to date in these 4 diseases. PMID:26668337

  5. New insights toward the discovery of antibacterial agents: multi-tasking QSBER model for the simultaneous prediction of anti-tuberculosis activity and toxicological profiles of drugs.

    PubMed

    Speck-Planche, Alejandro; Kleandrova, Valeria V; Cordeiro, M Natália D S

    2013-03-12

    Tuberculosis (TB) constitutes one of the most dangerous and serious health problems around the world. It is a very lethal disease caused by microorganisms of the genus mycobacterium, principally Mycobacterium tuberculosis (MTB) which affects humans. A very active field for the search of more efficient anti-TB chemotherapies is the use in silico methodologies for the discovery of potent anti-TB agents. The battle against MTB by using antimicrobial chemotherapies will depend on the design of new chemicals with high anti-TB activity and low toxicity as possible. Multi-target methodologies focused on quantitative-structure activity relationships (mt-QSAR) have played a very important role for the rationalization of drug design, providing a better understanding about the molecular patterns related with diverse pharmacological profiles including antimicrobial activity. Nowadays, almost all mt-QSAR models have considered the study of biological activity or toxicity separately. In the present study, we develop by the first time, a unified multitasking model based on quantitative-structure biological effect relationships (mtk-QSBER) for the simultaneous prediction of anti-TB activity and toxicity against Mus musculus and Rattus norvegicus. The mtk-QSBER model was created by using linear discriminant analysis (LDA) for the classification of compounds as positive (high biological activity and/or low toxicity) or negative (otherwise) under many experimental conditions. Our mtk-QSBER model, correctly classified more than 90% of the case in the whole database (more than 12,000 cases), serving as a powerful tool for the computer-assisted screening of potent and safe anti-TB drugs. PMID:23376211

  6. Drugs.

    ERIC Educational Resources Information Center

    Hurst, Hunter, Ed.; And Others

    1984-01-01

    This document contains the third volume of "Today's Delinquent," an annual publication of the National Center for Juvenile Justice. This volume deals with the issue of drugs and includes articles by leading authorities in delinquency and substance abuse who share their views on causes and cures for the drug problem among youth in this country.…

  7. Structures of Pseudomonas aeruginosa β-ketoacyl-(acyl-carrier-protein) synthase II (FabF) and a C164Q mutant provide templates for antibacterial drug discovery and identify a buried potassium ion and a ligand-binding site that is an artefact of the crystal form

    SciTech Connect

    Baum, Bernhard; Lecker, Laura S. M.; Zoltner, Martin; Jaenicke, Elmar; Schnell, Robert; Hunter, William N.; Brenk, Ruth

    2015-07-28

    Three crystal structures of recombinant P. aeruginosa FabF are reported: the apoenzyme, an active-site mutant and a complex with a fragment of a natural product inhibitor. The characterization provides reagents and new information to support antibacterial drug discovery. Bacterial infections remain a serious health concern, in particular causing life-threatening infections of hospitalized and immunocompromised patients. The situation is exacerbated by the rise in antibacterial drug resistance, and new treatments are urgently sought. In this endeavour, accurate structures of molecular targets can support early-stage drug discovery. Here, crystal structures, in three distinct forms, of recombinant Pseudomonas aeruginosa β-ketoacyl-(acyl-carrier-protein) synthase II (FabF) are presented. This enzyme, which is involved in fatty-acid biosynthesis, has been validated by genetic and chemical means as an antibiotic target in Gram-positive bacteria and represents a potential target in Gram-negative bacteria. The structures of apo FabF, of a C164Q mutant in which the binding site is altered to resemble the substrate-bound state and of a complex with 3-(benzoylamino)-2-hydroxybenzoic acid are reported. This compound mimics aspects of a known natural product inhibitor, platensimycin, and surprisingly was observed binding outside the active site, interacting with a symmetry-related molecule. An unusual feature is a completely buried potassium-binding site that was identified in all three structures. Comparisons suggest that this may represent a conserved structural feature of FabF relevant to fold stability. The new structures provide templates for structure-based ligand design and, together with the protocols and reagents, may underpin a target-based drug-discovery project for urgently needed antibacterials.

  8. Novel single-round PCR and cloning of full-length envelope genes of HIV-1 may yield new insight into biomolecular antibacterial drug development.

    PubMed

    McDonald, Richard; Burnett, Virginia

    2005-06-01

    Nested or semi-nested polymerase chain reaction (PCR) with a 'hot start' is the preferred amplification method for full-length, in-frame envelope genes (gp160) of the human immunodeficiency virus type 1 (HIV-1). This generally follows an extensive screening process. This paper describes an effective single-round PCR method and cloning process for HIV-1 gp160 from clinical samples, and cell and tissue cultures developed during the early stages of construction of a molecular HIV-1 vaccine. The amplification method and cloning process are adaptable to full-length HIV-1, HIV-2, and other viral production processes. Also described within, is one solution to the most-often extensive screening process for inserts containing full-length, in-frame gp160. Of note, was a perceived toxicity of gp160 to bacteria during the culturing and the scaling-up process that created the extensive screening process. The toxicity association was not found with the individual gp160 genes, the gp120 or the gp41 gene, with other viral regions similar or larger in molecular weight to gp160, or with other non-gp160 full-length genes of HIV-1 such as pol and gag genes. The HIV-1 gp160 toxicity issue may provide insight towards the development of the next generation of novel biomolecular drugs against bacterial infections. PMID:15847926

  9. Structure of a complex of uridine phosphorylase from Yersinia pseudotuberculosis with the modified bacteriostatic antibacterial drug determined by X-ray crystallography and computer analysis

    NASA Astrophysics Data System (ADS)

    Balaev, V. V.; Lashkov, A. A.; Gabdoulkhakov, A. G.; Seregina, T. A.; Dontsova, M. V.; Mikhailov, A. M.

    2015-03-01

    Pseudotuberculosis and bubonic plague are acute infectious diseases caused by the bacteria Yersinia pseudotuberculosis and Yersinia pestis. These diseases are treated, in particular, with trimethoprim and its modified analogues. However, uridine phosphorylases (pyrimidine nucleoside phosphorylases) that are present in bacterial cells neutralize the action of trimethoprim and its modified analogues on the cells. In order to reveal the character of the interaction of the drug with bacterial uridine phosphorylase, the atomic structure of the unligated molecule of uridine-specific pyrimidine nucleoside phosphorylase from Yersinia pseudotuberculosis ( YptUPh) was determined by X-ray diffraction at 1.7 Å resolution with high reliability ( R work = 16.2, R free = 19.4%; r.m.s.d. of bond lengths and bond angles are 0.006 Å and 1.005°, respectively; DPI = 0.107 Å). The atoms of the amino acid residues of the functionally important secondary-structure elements—the loop L9 and the helix H8—of the enzyme YptUPh were located. The three-dimensional structure of the complex of YptUPh with modified trimethoprim—referred to as 53I—was determined by the computer simulation. It was shown that 53I is a pseudosubstrate of uridine phosphorylases, and its pyrimidine-2,4-diamine group is located in the phosphate-binding site of the enzyme YptUPh.

  10. Green synthesis of silver nanoparticles from leaf extract of Mimusops elengi, Linn. for enhanced antibacterial activity against multi drug resistant clinical isolates.

    PubMed

    Prakash, P; Gnanaprakasam, P; Emmanuel, R; Arokiyaraj, S; Saravanan, M

    2013-08-01

    Green synthesis of metallic silver nanoparticles has attracted nowadays and alternative to physical and chemical approaches. In the present study, silver nanoparticles (AgNPs) were synthesized from leaf extract of Mimusops elengi, L. at room temperature. Formation of stable AgNPs at 1mM concentrations of silver nitrate (AgNO3) typically gave spherical shape particles with diameter range from 55 to 83nm. The kinetic properties of particle formation were proportional to the effect of concentration of AgNO3 solution. In order to identify the compounds responsible for the bioreduction of Ag(+) ion and the stabilization of AgNPs produced, the functional group present in Mimusops elengi, L. leaf extract was investigated using FTIR. The formation of nanoparticle was confirmed using the surface plasmon resonance band shown in UV-vis spectrophotometer. The topography and morphology of the particles were determined using scanning electron microscopy. The crystalline nature of nanoparticles was confirmed from the XRD pattern. Furthermore these green synthesized AgNPs were found to show higher antimicrobial efficacy against multi drug resistant clinical isolates. PMID:23563291

  11. Structure of a complex of uridine phosphorylase from Yersinia pseudotuberculosis with the modified bacteriostatic antibacterial drug determined by X-ray crystallography and computer analysis

    SciTech Connect

    Balaev, V. V.; Lashkov, A. A. Gabdoulkhakov, A. G.; Seregina, T. A.; Dontsova, M. V.; Mikhailov, A. M.

    2015-03-15

    Pseudotuberculosis and bubonic plague are acute infectious diseases caused by the bacteria Yersinia pseudotuberculosis and Yersinia pestis. These diseases are treated, in particular, with trimethoprim and its modified analogues. However, uridine phosphorylases (pyrimidine nucleoside phosphorylases) that are present in bacterial cells neutralize the action of trimethoprim and its modified analogues on the cells. In order to reveal the character of the interaction of the drug with bacterial uridine phosphorylase, the atomic structure of the unligated molecule of uridine-specific pyrimidine nucleoside phosphorylase from Yersinia pseudotuberculosis (YptUPh) was determined by X-ray diffraction at 1.7 Å resolution with high reliability (R{sub work} = 16.2, R{sub free} = 19.4%; r.m.s.d. of bond lengths and bond angles are 0.006 Å and 1.005°, respectively; DPI = 0.107 Å). The atoms of the amino acid residues of the functionally important secondary-structure elements—the loop L9 and the helix H8—of the enzyme YptUPh were located. The three-dimensional structure of the complex of YptUPh with modified trimethoprim—referred to as 53I—was determined by the computer simulation. It was shown that 53I is a pseudosubstrate of uridine phosphorylases, and its pyrimidine-2,4-diamine group is located in the phosphate-binding site of the enzyme YptUPh.

  12. Speculative strategies for new antibacterials: all roads should not lead to Rome.

    PubMed

    Shapiro, Stuart

    2013-07-01

    In concert with improvements in personal hygiene and public sanitation, the discovery and development of antibiotics during the latter half of the last century has reduced substantially the morbidity and mortality associated with bacterial diseases. However, the past decade has witnessed a sharp reduction in interest in antibacterial drug development by 'big pharma', compounded by a decline in the breadth of chemical space for new antibacterial molecules and a failure to exploit the plethora of cellular processes potentially targetable by novel classes of antibacterial molecules. This review focuses on some strategies relating to antibacterial chemotherapy, paths less trodden, which the author considers worthy of further exploration. PMID:23612725

  13. Identification of Additional Anti-Persister Activity against Borrelia burgdorferi from an FDA Drug Library.

    PubMed

    Feng, Jie; Weitner, Megan; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Zhang, Ying

    2015-01-01

    Lyme disease is a leading vector-borne disease in the United States. Although the majority of Lyme patients can be cured with standard 2-4 week antibiotic treatment, 10%-20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, persisting organisms not killed by current Lyme antibiotics may be involved. In our previous study, we screened an FDA drug library and reported 27 top hits that showed high activity against Borrelia persisters. In this study, we present the results of an additional 113 active hits that have higher activity against the stationary phase B. burgdorferi than the currently used Lyme antibiotics. Many antimicrobial agents (antibiotics, antivirals, antifungals, anthelmintics or antiparasitics) used for treating other infections were found to have better activity than the current Lyme antibiotics. These include antibacterials such as rifamycins (3-formal-rifamycin, rifaximin, rifamycin SV), thiostrepton, quinolone drugs (sarafloxacin, clinafloxacin, tosufloxacin), and cell wall inhibitors carbenicillin, tazobactam, aztreonam; antifungal agents such as fluconazole, mepartricin, bifonazole, climbazole, oxiconazole, nystatin; antiviral agents zanamivir, nevirapine, tilorone; antimalarial agents artemisinin, methylene blue, and quidaldine blue; antihelmintic and antiparasitic agents toltrazuril, tartar emetic, potassium antimonyl tartrate trihydrate, oxantel, closantel, hycanthone, pyrimethamine, and tetramisole. Interestingly, drugs used for treating other non-infectious conditions including verteporfin, oltipraz, pyroglutamic acid, pidolic acid, and dextrorphan tartrate, that act on the glutathione/γ-glutamyl pathway involved in protection against free radical damage, and also the antidepressant drug indatraline, were found to have high activity against stationary phase B. burgdorferi. Among the active hits, agents that affect cell membranes, energy production, and reactive oxygen species production are more active against the B. burgdorferi persisters than the commonly used antibiotics that inhibit macromolecule biosynthesis. Future studies are needed to evaluate and optimize the promising active hits in drug combination studies in vitro and also in vivo in animal models. These studies may have implications for developing more effective treatments of Lyme disease. PMID:27025631

  14. Identification of Additional Anti-Persister Activity against Borrelia burgdorferi from an FDA Drug Library

    PubMed Central

    Feng, Jie; Weitner, Megan; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Zhang, Ying

    2015-01-01

    Lyme disease is a leading vector-borne disease in the United States. Although the majority of Lyme patients can be cured with standard 2–4 week antibiotic treatment, 10%–20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, persisting organisms not killed by current Lyme antibiotics may be involved. In our previous study, we screened an FDA drug library and reported 27 top hits that showed high activity against Borrelia persisters. In this study, we present the results of an additional 113 active hits that have higher activity against the stationary phase B. burgdorferi than the currently used Lyme antibiotics. Many antimicrobial agents (antibiotics, antivirals, antifungals, anthelmintics or antiparasitics) used for treating other infections were found to have better activity than the current Lyme antibiotics. These include antibacterials such as rifamycins (3-formal-rifamycin, rifaximin, rifamycin SV), thiostrepton, quinolone drugs (sarafloxacin, clinafloxacin, tosufloxacin), and cell wall inhibitors carbenicillin, tazobactam, aztreonam; antifungal agents such as fluconazole, mepartricin, bifonazole, climbazole, oxiconazole, nystatin; antiviral agents zanamivir, nevirapine, tilorone; antimalarial agents artemisinin, methylene blue, and quidaldine blue; antihelmintic and antiparasitic agents toltrazuril, tartar emetic, potassium antimonyl tartrate trihydrate, oxantel, closantel, hycanthone, pyrimethamine, and tetramisole. Interestingly, drugs used for treating other non-infectious conditions including verteporfin, oltipraz, pyroglutamic acid, pidolic acid, and dextrorphan tartrate, that act on the glutathione/γ-glutamyl pathway involved in protection against free radical damage, and also the antidepressant drug indatraline, were found to have high activity against stationary phase B. burgdorferi. Among the active hits, agents that affect cell membranes, energy production, and reactive oxygen species production are more active against the B. burgdorferi persisters than the commonly used antibiotics that inhibit macromolecule biosynthesis. Future studies are needed to evaluate and optimize the promising active hits in drug combination studies in vitro and also in vivo in animal models. These studies may have implications for developing more effective treatments of Lyme disease. PMID:27025631

  15. Bypassing Fluoroquinolone Resistance with Quinazolinediones: Studies of Drug–Gyrase–DNA Complexes Having Implications for Drug Design

    PubMed Central

    2015-01-01

    Widespread fluoroquinolone resistance has drawn attention to quinazolinediones (diones), fluoroquinolone-like topoisomerase poisons that are unaffected by common quinolone-resistance mutations. To better understand differences between quinolones and diones, we examined their impact on the formation of cleaved complexes (drug–topoisomerase–DNA complexes in which the DNA moiety is broken) with gyrase, one of two bacterial targets of the drugs. Formation of cleaved complexes, measured by linearization of a circular DNA substrate, required lower concentrations of quinolone than dione. The reverse reaction, detected as resealing of DNA breaks in cleaved complexes, required higher temperatures and EDTA concentrations for quinolones than diones. The greater stability of quinolone-containing complexes was attributed to the unique ability of the quinolone C3/C4 keto acid to complex with magnesium and form a previously described drug–magnesium–water bridge with GyrA-Ser83 and GyrA-Asp87. A nearby substitution in GyrA (G81C) reduced activity differences between quinolone and dione, indicating that resistance due to this variation derives from perturbation of the magnesium–water bridge. To increase dione activity, we examined a relatively small, flexible C-7-3-(aminomethyl)pyrrolidinyl substituent, which is distal to the bridging C3/C4 keto acid substituent of quinolones. The 3-(aminomethyl)pyrrolidinyl group at position C-7 was capable of forming binding interactions with GyrB-Glu466, as indicated by inspection of crystal structures, computer-aided docking, and measurement of cleaved-complex formation with mutant and wild-type GyrB proteins. Thus, modification of dione C-7 substituents constitutes a strategy for obtaining compounds active against common quinolone-resistant mutants. PMID:25310082

  16. Structures of Pseudomonas aeruginosa β-ketoacyl-(acyl-carrier-protein) synthase II (FabF) and a C164Q mutant provide templates for antibacterial drug discovery and identify a buried potassium ion and a ligand-binding site that is an artefact of the crystal form

    PubMed Central

    Baum, Bernhard; Lecker, Laura S. M.; Zoltner, Martin; Jaenicke, Elmar; Schnell, Robert; Hunter, William N.; Brenk, Ruth

    2015-01-01

    Bacterial infections remain a serious health concern, in particular causing life-threatening infections of hospitalized and immunocompromised patients. The situation is exacerbated by the rise in antibacterial drug resistance, and new treatments are urgently sought. In this endeavour, accurate structures of molecular targets can support early-stage drug discovery. Here, crystal structures, in three distinct forms, of recombinant Pseudomonas aeruginosa β-ketoacyl-(acyl-carrier-protein) synthase II (FabF) are presented. This enzyme, which is involved in fatty-acid biosynthesis, has been validated by genetic and chemical means as an antibiotic target in Gram-positive bacteria and represents a potential target in Gram-negative bacteria. The structures of apo FabF, of a C164Q mutant in which the binding site is altered to resemble the substrate-bound state and of a complex with 3-(benzoylamino)-2-hydroxybenzoic acid are reported. This compound mimics aspects of a known natural product inhibitor, platensimycin, and surprisingly was observed binding outside the active site, interacting with a symmetry-related molecule. An unusual feature is a completely buried potassium-binding site that was identified in all three structures. Comparisons suggest that this may represent a conserved structural feature of FabF relevant to fold stability. The new structures provide templates for structure-based ligand design and, together with the protocols and reagents, may underpin a target-based drug-discovery project for urgently needed antibacterials. PMID:26249693

  17. Antibacterial properties and mechanisms of gold-silver nanocages.

    PubMed

    Wang, Yulan; Wan, Jiangshan; Miron, Richard J; Zhao, Yanbin; Zhang, Yufeng

    2016-06-01

    Despite the number of antibiotics used in routine clinical practice, bacterial infections continue to be one of the most important challenges faced in humans. The main concerns arise from the continuing emergence of antibiotic-resistant bacteria and the difficulties faced with the pharmaceutical development of new antibiotics. Thus, advancements in the avenue of novel antibacterial agents are essential. In this study, gold (Au) was combined with silver (Ag), a well-known antibacterial material, to form silver nanoparticles producing a gold-silver alloy structure with hollow interiors and porous walls (gold-silver nanocage). This novel material was promising in antibacterial applications due to its better biocompatibility than Ag nanoparticles, potential in photothermal effects and drug delivery ability. The gold-silver nanocage was then tested for its antibacterial properties and the mechanism involved leading to its antibacterial properties. This study confirms that this novel gold-silver nanocage has broad-spectrum antibacterial properties exerting its effects through the destruction of the cell membrane, production of reactive oxygen species (ROS) and induction of cell apoptosis. Therefore, we introduce a novel gold-silver nanocage that serves as a potential nanocarrier for the future delivery of antibiotics. PMID:27180869

  18. Xenobiotic biotransformation of 4-methoxy-N-methyl-2-quinolone, isolated from Zanthoxylum monophyllum.

    PubMed

    Rodrguez-Guzmn, Raquel; Radwan, Mohamed M; Burandt, Charles L; Williamson, John S; Ross, Samir A

    2010-09-01

    Phytochemical evaluation of Zanthoxylum monophyllum has led to the isolation of the alkaloid 4-methoxy-N-methyl-2-quinolone (1) with a significant activity against methicillin-resistant Staphylococcus aureus (MRSA), with an IC50 value of 1.5 microg/mL. Xenobiotic biotransformation of 1 has been conducted with the general goal of increasing the bioactivity of the compound and contributing new leads for further pharmacological research. Twenty-nine microorganisms were used for screening and two (Aspergillus flavus and Cunninghamella echinulata var. echinulata) were able to transform compound 1 to 4-methoxy-2-quinolone (2). Structural identification of the compounds was based on NMR, IR, and MS data. PMID:20923009

  19. nfxC-type quinolone resistance in a clinical isolate of Pseudomonas aeruginosa.

    PubMed Central

    Fukuda, H; Hosaka, M; Iyobe, S; Gotoh, N; Nishino, T; Hirai, K

    1995-01-01

    Quinolone resistance gene nqr-T91 in a clinical isolate of Pseudomonas aeruginosa P1481 was cotransducible with catA1 in P. aeruginosa PAO. The nqr-T91 transductant, PKH-T91, was resistant to norfloxacin, imipenem, and chloramphenicol and showed less norfloxacin accumulation than the parent strain did. Loss of the 46-kDa outer membrane protein (D2) and an increase in the 50-kDa outer membrane protein in PKH-T91 were observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Lipopolysaccharides in the transductant were also changed. These alterations were considered to be related to lower levels of norfloxacin accumulation in PKH-T91. These genetic and biochemical properties suggested that an nfxC type of quinolone-resistant mutation occurred in a clinical isolate of P. aeruginosa P1481. PMID:7793896

  20. Superhydrophobic antibacterial cotton textiles.

    PubMed

    Shateri Khalil-Abad, Mohammad; Yazdanshenas, Mohammad E

    2010-11-01

    We present a facile and effective method to prepare superhydrophobic cotton textiles. Silver particles were produced on cotton fibers by treatment with aqueous KOH and AgNO(3), followed by reduction treatment with ascorbic acid in the presence of a polymeric steric stabilizer to generate a dual-size surface roughness. Further modification of the particle-containing cotton textiles with octyltriethoxysilane led to hydrophobic surfaces. Surfaces prepared showed a sticky property, which exhibits a static water contact angle of 151 degrees for a 10 microL droplet that water drop did not slid off even when the sample was held upside down. The modified cotton has potent antibacterial activity toward both Gram-positive and Gram-negative bacteria. The Ag particles were uniformly and stably distributed on the substrate surface and killed bacteria. These modified cotton textiles are potentially useful; as superhydrophobic antibacterial fabrics in a wide variety of biomedical and general use applications. PMID:20709327

  1. Dose escalation study of the safety, tolerability, and pharmacokinetics of nemonoxacin (TG-873870), a novel potent broad-spectrum nonfluorinated quinolone, in healthy volunteers.

    PubMed

    Lin, Luke; Chang, Li-Wen; Tsai, Cheng-Yuan; Hsu, Ching-Hung; Chung, David T; Aronstein, William S; Ajayi, Funmi; Kuzmak, Barbara; Lyon, Robert A

    2010-01-01

    Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with potent broad-spectrum activity against Gram-positive and Gram-negative pathogens, including methicillin-resistant Staphylococcus aureus, penicillin- and quinolone-resistant Streptococcus pneumoniae, and vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus. The safety, tolerability, and pharmacokinetics of nemonoxacin were investigated in a double-blind, ascending-single-dose study involving 56 healthy subjects (48 males and 8 females) who were randomly assigned to 1 of 7 dose cohorts. In each successive cohort, two subjects received a placebo and six received single oral doses of 25, 50, 125, 250, 500, 1,000, or 1,500 mg nemonoxacin. Nemonoxacin was well tolerated up to the maximum dose of 1,500 mg. No severe or serious adverse events were observed. The most frequent adverse events were contact dermatitis, pruritus, and erythema. No clinically significant abnormalities were noted in the electrocardiograms, vital signs, or laboratory tests. The plasma concentrations increased over the dose range, and at 500 mg, the free area under the plasma concentration-time curve/MIC(90) ratios and free maximum nemonoxacin concentration/MIC(90) ratios against drug-sensitive/drug-resistant S. pneumoniae and S. aureus were greater than 227 and 24, respectively. The peak time and elimination half-life of nemonoxacin were 1 to 2 h and 9 to 16 h, respectively. The oral clearance was approximately 0.22 liter/h/kg. The plasma protein binding was approximately 16%. The results of this study support further evaluation of the multiple-dose safety, tolerability, and pharmacokinetics of nemonoxacin. PMID:19884368

  2. Dose Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Nemonoxacin (TG-873870), a Novel Potent Broad-Spectrum Nonfluorinated Quinolone, in Healthy Volunteers?

    PubMed Central

    Lin, Luke; Chang, Li-Wen; Tsai, Cheng-Yuan; Hsu, Ching-Hung; Chung, David T.; Aronstein, William S.; Ajayi, Funmi; Kuzmak, Barbara; Lyon, Robert A.

    2010-01-01

    Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with potent broad-spectrum activity against Gram-positive and Gram-negative pathogens, including methicillin-resistant Staphylococcus aureus, penicillin- and quinolone-resistant Streptococcus pneumoniae, and vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus. The safety, tolerability, and pharmacokinetics of nemonoxacin were investigated in a double-blind, ascending-single-dose study involving 56 healthy subjects (48 males and 8 females) who were randomly assigned to 1 of 7 dose cohorts. In each successive cohort, two subjects received a placebo and six received single oral doses of 25, 50, 125, 250, 500, 1,000, or 1,500 mg nemonoxacin. Nemonoxacin was well tolerated up to the maximum dose of 1,500 mg. No severe or serious adverse events were observed. The most frequent adverse events were contact dermatitis, pruritus, and erythema. No clinically significant abnormalities were noted in the electrocardiograms, vital signs, or laboratory tests. The plasma concentrations increased over the dose range, and at 500 mg, the free area under the plasma concentration-time curve/MIC90 ratios and free maximum nemonoxacin concentration/MIC90 ratios against drug-sensitive/drug-resistant S. pneumoniae and S. aureus were greater than 227 and 24, respectively. The peak time and elimination half-life of nemonoxacin were 1 to 2 h and 9 to 16 h, respectively. The oral clearance was approximately 0.22 liter/h/kg. The plasma protein binding was approximately 16%. The results of this study support further evaluation of the multiple-dose safety, tolerability, and pharmacokinetics of nemonoxacin. PMID:19884368

  3. Two distinct pathways supply anthranilate as a precursor of the Pseudomonas quinolone signal.

    PubMed

    Farrow, John M; Pesci, Everett C

    2007-05-01

    Pseudomonas aeruginosa is an opportunistic pathogen that causes serious infections in immunocompromised patients and those with cystic fibrosis (CF). This gram-negative bacterium uses multiple cell-to-cell signals to control numerous cellular functions and virulence. One of these signals is 2-heptyl-3-hydroxy-4-quinolone, which is referred to as the Pseudomonas quinolone signal (PQS). This signal functions as a coinducer for a transcriptional regulator (PqsR) to positively control multiple virulence genes and its own synthesis. PQS production is required for virulence in multiple models of infection, and it has been shown to be produced in the lungs of CF patients infected by P. aeruginosa. One of the precursor compounds from which PQS is synthesized is the metabolite anthranilate. This compound can be derived from the conversion of chorismate to anthranilate by an anthranilate synthase or through the degradation of tryptophan via the anthranilate branch of the kynurenine pathway. In this study, we present data which help to define the kynurenine pathway in P. aeruginosa and show that the kynurenine pathway serves as a critical source of anthranilate for PQS synthesis. We also show that the kyn pathway genes are induced during growth with tryptophan and that they are autoregulated by kynurenine. This study provides solid foundations for the understanding of how P. aeruginosa produces the anthranilate that serves as a precursor to PQS and other 4-quinolones. PMID:17337571

  4. Characterization of quinolone resistance in Salmonella spp. isolates from food products and human samples in Brazil

    PubMed Central

    Pribul, Bruno Rocha; Festivo, Marcia Lima; de Souza, Miliane Moreira Soares; dos Prazeres Rodrigues, Dalia

    2016-01-01

    Non-typhoidal salmonellosis is an important zoonotic disease caused by Salmonella enterica. The aim of this study was to investigate the prevalence of plasmid-mediated quinolone resistance in Salmonella spp. and its association with fluoroquinolone susceptibility in Brazil. A total of 129 NTS isolates (samples from human origin, food from animal origin, environmental, and animal) grouped as from animal (n = 62) and human (n = 67) food were evaluated between 2009 and 2013. These isolates were investigated through serotyping, antimicrobial susceptibility testing, and the presence of plasmid-mediated quinolone resistance (PMQR) genes (qnr, aac(6′)-Ib) and associated integron genes (integrase, and conserved integron region). Resistance to quinolones and/or fluoroquinolones, from first to third generations, was observed. Fifteen isolates were positive for the presence of qnr genes (8 qnrS, 6 qnrB, and 1 qnrD) and twenty three of aac(6′)-Ib. The conserved integron region was detected in 67 isolates as variable regions, from ±600 to >1000 pb. The spread of NTS involving PMQR carriers is of serious concern and should be carefully monitored. PMID:26887245

  5. Characterization of quinolone resistance in Salmonella spp. isolates from food products and human samples in Brazil.

    PubMed

    Pribul, Bruno Rocha; Festivo, Marcia Lima; de Souza, Miliane Moreira Soares; Dos Prazeres Rodrigues, Dalia

    2016-01-01

    Non-typhoidal salmonellosis is an important zoonotic disease caused by Salmonella enterica. The aim of this study was to investigate the prevalence of plasmid-mediated quinolone resistance in Salmonella spp. and its association with fluoroquinolone susceptibility in Brazil. A total of 129 NTS isolates (samples from human origin, food from animal origin, environmental, and animal) grouped as from animal (n=62) and human (n=67) food were evaluated between 2009 and 2013. These isolates were investigated through serotyping, antimicrobial susceptibility testing, and the presence of plasmid-mediated quinolone resistance (PMQR) genes (qnr, aac(6')-Ib) and associated integron genes (integrase, and conserved integron region). Resistance to quinolones and/or fluoroquinolones, from first to third generations, was observed. Fifteen isolates were positive for the presence of qnr genes (8 qnrS, 6 qnrB, and 1 qnrD) and twenty three of aac(6')-Ib. The conserved integron region was detected in 67 isolates as variable regions, from ±600 to >1000pb. The spread of NTS involving PMQR carriers is of serious concern and should be carefully monitored. PMID:26887245

  6. Renaissance of antibiotics against difficult infections: Focus on oritavancin and new ketolides and quinolones.

    PubMed

    Van Bambeke, Franoise

    2014-11-01

    Lipoglycopeptide, ketolide, and quinolone antibiotics are currently in clinical development, with specific advantages over available molecules within their respective classes. The lipoglycopeptide oritavancin is bactericidal against MRSA, vancomycin-resistant enterococci, and multiresistant Streptococcus pneumoniae, and proved effective and safe for the treatment of acute bacterial skin and skin structure infection (ABSSSI) upon administration of a single 1200 mg dose (two completed phase III trials). The ketolide solithromycin (two phase III studies recruiting for community-acquired pneumonia) shows a profile of activity similar to that of telithromycin, but in vitro data suggest a lower risk of hepatotoxicity, visual disturbance, and aggravation of myasthenia gravis due to reduced affinity for nicotinic receptors. Among quinolones, finafloxacin and delafloxacin share the unique property of an improved activity in acidic environments (found in many infection sites). Finafloxacin (phase II completed; activity profile similar to that of ciprofloxacin) is evaluated for complicated urinary tract and Helicobacter pylori infections. The other quinolones (directed towards Gram-positive pathogens) show improved activity on MRSA and multiresistant S. pneumoniae compared to current molecules. They are in clinical evaluation for ABSSSI (avarofloxacin (phase II completed), nemonoxacin and delafloxacin (ongoing phase III)), respiratory tract infections (zabofloxacin and nemonoxacin (ongoing phase III)), or gonorrhea (delafloxacin). PMID:25058176

  7. [Advance in studies on antibacterial effect of flavonoids].

    PubMed

    You, Ting-Huo; Liu, Fan; Wen, Lu; Zou, Yu-Xiao; Liao, Sen-Tai; Xiao, Geng-Sheng

    2013-11-01

    As antibiotic drug resistance has become one of the most serious threats to global public health, there is a pressing need to look for new effective therapeutic drugs. Flavonoids are a large class of chemicals widely exist in plants, and have such effects as direct antibiotics, synergistic antibiotics and inhibition of bacterial activity. In this article, we made a summary for the advance in studies on the antibacterial effects of flavonoids and their mechanism. PMID:24494547

  8. The discovery of antibacterial agents using diversity-oriented synthesis.

    PubMed

    Galloway, Warren R J D; Bender, Andreas; Welch, Martin; Spring, David R

    2009-05-14

    The emergence and increasing prevalence of multi-drug resistance bacterial strains represents a clear and present danger to the standard of human healthcare as we know it. The systematic study of modulating biological systems using small molecules (so-called chemical genetics) offers a potentially fruitful means of discovering critically needed new antibacterial agents. Crucial to the success of this approach is the ready availability of functionally diverse small molecule collections. In this feature article we focus upon the use of a diversity-oriented synthesis (DOS) approach for the efficient generation of such compound collections, and discuss the utility of DOS for the discovery of new antibacterial agents. PMID:19532856

  9. Characterization of ESBLs and associated quinolone resistance in Escherichia coli and Klebsiella pneumoniae isolates from an urban wastewater treatment plant in Algeria.

    PubMed

    Alouache, Souhila; Estepa, Vanesa; Messai, Yamina; Ruiz, Elena; Torres, Carmen; Bakour, Rabah

    2014-02-01

    The aim of the study was the characterization of extended spectrum beta-lactamases (ESBLs) and quinolone resistance in cefotaxime-resistant coliform isolates from a wastewater treatment plant (WWTP). ESBLs were detected in 19 out of 24 isolates (79%) from raw water and in 21 out of 24 isolates (87.5%) from treated water, identified as Klebsiella pneumoniae and Escherichia coli. Molecular characterization of ESBLs and quinolone resistance showed allele profiles CTX-M-15 (3), CTX-M-3 (5), CTX-M-15+qnrB1 (1), CTX-M-3+qnrB1 (1), CTX-M-15+aac-(6')-Ib-cr (4), and CTX-M-15+qnrB1+aac-(6')-Ib-cr (7). A double mutation S83L and D87N (GyrA) and a single mutation S80I (ParC) were detected in ciprofloxacin-resistant E. coli isolates. In K. pneumoniae, mutations S83I (GyrA)+S80I (ParC) or single S80I mutation were detected in ciprofloxacin-resistant isolates, and no mutation was observed in ciprofloxacin-susceptible isolates. bla(CTX-M), qnrB1, and aac-(6')-Ib-cr were found, respectively, in these genetic environments: ISEcp1-bla(CTX-M)-orf477, orf1005-orf1-qnrB1, and Tn1721-IS26-aac-(6')-Ib-cr-bla(OXA-1)-catB4. bla(CTX-M-15) was located on IncF plasmid in E. coli and bla(CTX-M-3) on IncL/M plasmid in both species (E. coli and K. pneumoniae). E. coli isolates were affiliated to the phylogroups/MLST: D/ST405 (CC405), A/ST10 (CC10), A/ST617 (CC10), and B1/ST1431. K. pneumoniae isolates belonged to phylogroup KpI and to sequence types ST15, ST17, ST36, ST48, ST54, and ST147. The study showed a multi-drug resistance at the inflow and outflow of the WWTP, with ESBL production, plasmid-mediated quinolones resistance, and mutations in topoisomerases. The findings highlight the similarity of antibiotic resistance mechanisms in the clinical setting and the environment, and the role of the latter as a source of dissemination of resistance genes. PMID:23952363

  10. Antibacterial agents--phagocytes: new concepts for old in immunomodulation.

    TOXLINE Toxicology Bibliographic Information

    Labro MT

    1998-04-01

    The possibility that antibacterial agents, primarily directed against microorganisms, also modify host functions is widely recognized. While a knowledge of these non-antimicrobial effects of antibiotics, sometimes considered as 'side-effects', is necessary to prevent antibiotic-associated toxicity, the development of drugs derived from antibacterial agents for use in non-infectious diseases (e.g. motilins and antidiabetic drugs) is a new field of therapeutic research. Interactions between antibacterial drugs and the immune system may contribute to therapeutic efficacy in infectious diseases [1,2]. The immune system itself is a complex pyramid of redundant cellular factors/humoral effectors/mediators, whose fine regulation is just beginning to be unraveled. Phagocytes, ubiquitous and multifaceted cells are key components of cellular immunity, being involved both in immediate defences against non-self targets (pathogens, tumour cells, exogenous molecules, etc.) and in the regulation and triggering of specific immune responses. They are thus, prime targets of immune response modifiers. This review reconsiders the widely explored problem of interactions between antibacterial agents and phagocytes, focusing on future prospects in both infectious and non-infectious diseases.

  11. Antibacterial Diamines Targeting Bacterial Membranes.

    PubMed

    Wang, Bo; Pachaiyappan, Boobalan; Gruber, Jordon D; Schmidt, Michael G; Zhang, Yong-Mei; Woster, Patrick M

    2016-04-14

    Antibiotic resistance is a growing threat to human health exacerbated by a lack of new antibiotics. We now describe a series of substituted diamines that produce rapid bactericidal activity against both Gram-positive and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus and stationary-phase bacteria. These compounds reduce biofilm formation and promote biofilm dispersal in Pseudomonas aeruginosa. The most potent analogue, 3 (1,13-bis{[(2,2-diphenyl)-1-ethyl]thioureido}-4,10-diazatridecane), primarily acts by depolarization of the cytoplasmic membrane and permeabilization of the bacterial outer membrane. Transmission electron microscopy confirmed that 3 disrupts membrane integrity rapidly. Compound 3 is also synergistic with kanamycin, demonstrated by the checkerboard method and by time-kill kinetic experiments. In human cell toxicity assays, 3 showed limited adverse effects against the HEK293T human kidney embryonic cells and A549 human adenocarcinoma cells. In addition, 3 produced no adverse effects on Caenorhabditis elegans development, survival, and reproduction. Collectively, diamines related to 3 represent a new class of broad-spectrum antibacterials against drug-resistant pathogens. PMID:26964758

  12. Antibacterial Au nanostructured surfaces

    NASA Astrophysics Data System (ADS)

    Wu, Songmei; Zuber, Flavia; Brugger, Juergen; Maniura-Weber, Katharina; Ren, Qun

    2016-01-01

    We present here a technological platform for engineering Au nanotopographies by templated electrodeposition on antibacterial surfaces. Three different types of nanostructures were fabricated: nanopillars, nanorings and nanonuggets. The nanopillars are the basic structures and are 50 nm in diameter and 100 nm in height. Particular arrangement of the nanopillars in various geometries formed nanorings and nanonuggets. Flat surfaces, rough substrate surfaces, and various nanostructured surfaces were compared for their abilities to attach and kill bacterial cells. Methicillin-resistant Staphylococcus aureus, a Gram-positive bacterial strain responsible for many infections in health care system, was used as the model bacterial strain. It was found that all the Au nanostructures, regardless their shapes, exhibited similar excellent antibacterial properties. A comparison of live cells attached to nanotopographic surfaces showed that the number of live S. aureus cells was <1% of that from flat and rough reference surfaces. Our micro/nanofabrication process is a scalable approach based on cost-efficient self-organization and provides potential for further developing functional surfaces to study the behavior of microbes on nanoscale topographies.We present here a technological platform for engineering Au nanotopographies by templated electrodeposition on antibacterial surfaces. Three different types of nanostructures were fabricated: nanopillars, nanorings and nanonuggets. The nanopillars are the basic structures and are 50 nm in diameter and 100 nm in height. Particular arrangement of the nanopillars in various geometries formed nanorings and nanonuggets. Flat surfaces, rough substrate surfaces, and various nanostructured surfaces were compared for their abilities to attach and kill bacterial cells. Methicillin-resistant Staphylococcus aureus, a Gram-positive bacterial strain responsible for many infections in health care system, was used as the model bacterial strain. It was found that all the Au nanostructures, regardless their shapes, exhibited similar excellent antibacterial properties. A comparison of live cells attached to nanotopographic surfaces showed that the number of live S. aureus cells was <1% of that from flat and rough reference surfaces. Our micro/nanofabrication process is a scalable approach based on cost-efficient self-organization and provides potential for further developing functional surfaces to study the behavior of microbes on nanoscale topographies. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr06157a

  13. High-level quinolone resistance is associated with the overexpression of smeVWX in Stenotrophomonas maltophilia clinical isolates.

    PubMed

    García-León, G; Ruiz de Alegría Puig, C; García de la Fuente, C; Martínez-Martínez, L; Martínez, J L; Sánchez, M B

    2015-05-01

    Stenotrophomonas maltophilia is the only known bacterium in which quinolone-resistant isolates do not present mutations in the genes encoding bacterial topoisomerases. The expression of the intrinsic quinolone resistance elements smeDEF, smeVWX and Smqnr was analysed in 31 clinical S. maltophilia isolates presenting a minimum inhibitory concentration (MIC) range to ciprofloxacin between 0.5 and > 32 μg/mL; 11 (35.5%) overexpressed smeDEF, 2 (6.5%) presenting the highest quinolone MICs overexpressed smeVWX and 1 (3.2%) overexpressed Smqnr. Both strains overexpressing smeVWX presented changes at the Gly266 position of SmeRv, the repressor of smeVWX. Changes at the same position were previously observed in in vitro selected S. maltophilia quinolone-resistant mutants, indicating this amino acid is highly relevant for the activity of SmeRv in repressing smeVWX expression. For the first time SmeVWX overexpression is associated with quinolone resistance of S. maltophilia clinical isolates. PMID:25753190

  14. Molecular mechanisms of quinolone, macrolide, and tetracycline resistance among Campylobacter isolates from initial stages of broiler production.

    PubMed

    Pérez-Boto, D; Herrera-León, S; García-Peña, F J; Abad-Moreno, J C; Echeita, M A

    2014-01-01

    The aim of this study was to investigate the resistance mechanisms of quinolones, macrolides and tetracycline in campylobacter isolates from grandparent and parent broiler breeders in Spain. Twenty-six isolates were investigated for quinolone resistance, three isolates for macrolide resistance and 39 for tetracycline resistance. All of the quinolone-resistant isolates possessed the mutation Thr86Ile in the quinolone resistance-determining region of gyrA and one isolate possessed the mutation Pro104Ser. Only one Campylobacter coli population (defined by restriction fragment length polymorphism-polymerase chain reaction of flaA and pulsed field gel electrophoresis) was resistant to erythromycin, and the mutation A2075G (23S rDNA) was responsible for macrolide resistance. The tetO gene was found in all of the tetracycline-resistant isolates. Twenty-two out of the 39 isolates investigated by Southern blot possessed chromosomic location of tetO and 17 were located on plasmids. Most of the plasmids with tetO were of around 60 kb and conjugation was demonstrated in a selection of them. In conclusion, we showed that Thr86Ile is highly prevalent in quinolone-resistant isolates as well as mutation A2075G in macrolide-resistant isolates of poultry origin. More variability was found for tetO. The possibility of horizontal transmission of tetO among campylobacter isolates is also an issue of concern in public health. PMID:24689432

  15. Recent Development of Benzimidazole-Containing Antibacterial Agents.

    PubMed

    Song, Di; Ma, Shutao

    2016-04-01

    Clinically significant antibiotic resistance is one of the greatest challenges of the twenty-first century. However, new antibacterial agents are currently being developed at a much slower pace than our growing need for such drugs. Given their diverse biological activities and clinical applications, many bioactive heterocyclic compounds containing a benzimidazole nucleus have been the focus of interest for many researchers. The benzimidazole nucleus is a structural isostere of naturally occurring nucleotides. This advantage allows benzimidazoles to readily interact with the various biopolymers found in living systems. In view of this situation, much attention has been given to the exploration of benzimidazole-based antibacterial agents, leading to the discovery of many new chemical entities with intriguing profiles. In this minireview we summarize novel benzimidazole derivatives active against various bacterial strains. In particular, we outline the relationship between the structures of variously modified benzimidazoles and their antibacterial activity. PMID:26970352

  16. Antibacterial Au nanostructured surfaces.

    PubMed

    Wu, Songmei; Zuber, Flavia; Brugger, Juergen; Maniura-Weber, Katharina; Ren, Qun

    2016-01-28

    We present here a technological platform for engineering Au nanotopographies by templated electrodeposition on antibacterial surfaces. Three different types of nanostructures were fabricated: nanopillars, nanorings and nanonuggets. The nanopillars are the basic structures and are 50 nm in diameter and 100 nm in height. Particular arrangement of the nanopillars in various geometries formed nanorings and nanonuggets. Flat surfaces, rough substrate surfaces, and various nanostructured surfaces were compared for their abilities to attach and kill bacterial cells. Methicillin-resistant Staphylococcus aureus, a Gram-positive bacterial strain responsible for many infections in health care system, was used as the model bacterial strain. It was found that all the Au nanostructures, regardless their shapes, exhibited similar excellent antibacterial properties. A comparison of live cells attached to nanotopographic surfaces showed that the number of live S. aureus cells was <1% of that from flat and rough reference surfaces. Our micro/nanofabrication process is a scalable approach based on cost-efficient self-organization and provides potential for further developing functional surfaces to study the behavior of microbes on nanoscale topographies. PMID:26648134

  17. Acylated flavonol glycosides from Tagetes minuta with antibacterial activity

    PubMed Central

    Shahzadi, Irum; Shah, Mohammad M.

    2015-01-01

    Wild marigold (Tagetes minuta), a flowering plant of the family Asteraceae contains compounds of pharmaceutical and nutritional importance especially essential oils and flavonols. Identification, characterization of flavonols and determination of their antibacterial activity were major objectives of the current study. The isolation and purification of flavonols was accomplished using chromatographic techniques while structural elucidation was completed by LC–MS and NMR spectroscopy. The extracts and purified compounds were tested against various bacterial strains for antibacterial activity. A total of 19 flavonols were isolated from this species. Of these, 17 were of butanol and two of ethyl acetate extracts. Based on the concentration and purity, eight potential flavonols were selected and structurally elucidated. Four flavonols, 6-hydroxyquercetin 7-O-β-(6′′-galloylglucopyranoside; 2), 6-hydroxykaempferol 7-O-β-glucopyranoside (5), 6-hydroxykaempferol 7-O-β-(6′′-galloylglucopyranoside; 7), 6-hydroxyquercetin 7-O-β-(6′′-caffeoylglucopyranoside; 9), were identified for the first time from T. minuta. Butanol and ethyl acetate extracts of flowers and seeds showed significant antibacterial activity against Micrococcus leteus, Staphylococcus aureus, Bacillus subtilis, and Pseudomonas pikettii. Among the isolated flavonols only 1, 2, and 18 were found to possess significant antibacterial activity against M. luteus. The extracts and purified flavonols from T. minuta can be potential candidates for antibacterial drug discovery and support to ethnopharmacological use. PMID:26441652

  18. Antibacterial polyelectrolyte-coated Mg alloys for biomedical applications

    NASA Astrophysics Data System (ADS)

    Seraz, Md. S.; Asmatulu, R.; Chen, Z.; Ceylan, M.; Mahapatro, A.; Yang, S. Y.

    2014-04-01

    This study deals with two biomedical subjects: corrosion rates of polyelectrolyte-coated magnesium (Mg) alloys, mainly used for biomedical purposes, and antibacterial properties of these alloys. Thin sheets of Mg alloys were coated with cationic polyelectrolyte chitosan (CHI) and anionic polyelectrolyte carboxymethyl cellulose (CMC) using a layer-by-layer coating method and then embedded with antibacterial agents under vacuum. Electrochemical impedance spectroscopy was employed to analyze these samples in order to detect their corrosion properties at different conditions. In the electrochemical analysis section, a corrosion rate of 72 mille inches per year was found in a salt solution for the sample coated with a 12 phosphonic acid self-assembled monolayer and 9 CHI/CMC multilayers. In the antibacterial tests, gentamicin was used to investigate the effects of the drug embedded with the coated surfaces against the Escherichia coli (E. coli) bacteria. Antibacterial studies were tested using the disk diffusion method. Based on the standard diameter of the zone of inhibition chart, the antibacterial diffusion from the surface strongly inhibited bacterial growth in the regions. The largest recorded diameter of the zone of inhibition was 50 mm for the pre-UV treated and gentamicin-loaded sample, which is more than three times the standard diameter.

  19. Silver nanoparticles as potential antibacterial agents.

    PubMed

    Franci, Gianluigi; Falanga, Annarita; Galdiero, Stefania; Palomba, Luciana; Rai, Mahendra; Morelli, Giancarlo; Galdiero, Massimiliano

    2015-01-01

    Multi-drug resistance is a growing problem in the treatment of infectious diseases and the widespread use of broad-spectrum antibiotics has produced antibiotic resistance for many human bacterial pathogens. Advances in nanotechnology have opened new horizons in nanomedicine, allowing the synthesis of nanoparticles that can be assembled into complex architectures. Novel studies and technologies are devoted to understanding the mechanisms of disease for the design of new drugs, but unfortunately infectious diseases continue to be a major health burden worldwide. Since ancient times, silver was known for its anti-bacterial effects and for centuries it has been used for prevention and control of disparate infections. Currently nanotechnology and nanomaterials are fully integrated in common applications and objects that we use every day. In addition, the silver nanoparticles are attracting much interest because of their potent antibacterial activity. Many studies have also shown an important activity of silver nanoparticles against bacterial biofilms. This review aims to summarize the emerging efforts to address current challenges and solutions in the treatment of infectious diseases, particularly the use of nanosilver antimicrobials. PMID:25993417

  20. Rhodococcus erythropolis BG43 Genes Mediating Pseudomonas aeruginosa Quinolone Signal Degradation and Virulence Factor Attenuation

    PubMed Central

    Müller, Christine; Birmes, Franziska S.; Rückert, Christian; Kalinowski, Jörn

    2015-01-01

    Rhodococcus erythropolis BG43 is able to degrade the Pseudomonas aeruginosa quorum sensing signal molecules PQS (Pseudomonas quinolone signal) [2-heptyl-3-hydroxy-4(1H)-quinolone] and HHQ [2-heptyl-4(1H)-quinolone] to anthranilic acid. Based on the hypothesis that degradation of HHQ might involve hydroxylation to PQS followed by dioxygenolytic cleavage of the heterocyclic ring and hydrolysis of the resulting N-octanoylanthranilate, the genome was searched for corresponding candidate genes. Two gene clusters, aqdA1B1C1 and aqdA2B2C2, each predicted to code for a hydrolase, a flavin monooxygenase, and a dioxygenase related to 1H-3-hydroxy-4-oxoquinaldine 2,4-dioxygenase, were identified on circular plasmid pRLCBG43 of strain BG43. Transcription of all genes was upregulated by PQS, suggesting that both gene clusters code for alkylquinolone-specific catabolic enzymes. An aqdR gene encoding a putative transcriptional regulator, which was also inducible by PQS, is located adjacent to the aqdA2B2C2 cluster. Expression of aqdA2B2C2 in Escherichia coli conferred the ability to degrade HHQ and PQS to anthranilic acid; however, for E. coli transformed with aqdA1B1C1, only PQS degradation was observed. Purification of the recombinant AqdC1 protein verified that it catalyzes the cleavage of PQS to form N-octanoylanthranilic acid and carbon monoxide and revealed apparent Km and kcat values for PQS of ∼27 μM and 21 s−1, respectively. Heterologous expression of the PQS dioxygenase gene aqdC1 or aqdC2 in P. aeruginosa PAO1 quenched the production of the virulence factors pyocyanin and rhamnolipid and reduced the synthesis of the siderophore pyoverdine. Thus, the toolbox of quorum-quenching enzymes is expanded by new PQS dioxygenases. PMID:26319870

  1. Effect of DNA gyrase inhibitors pefloxacin, five other quinolones, novobiocin, and clorobiocin on Escherichia coli topoisomerase I.

    PubMed Central

    Tabary, X; Moreau, N; Dureuil, C; Le Goffic, F

    1987-01-01

    Two coumarins, inhibitors of the B subunit of DNA gyrase, and six quinolones, inhibitors of the A subunit, were tested against Escherichia coli topoisomerase I-catalyzed DNA relaxation. Coumarins had no effect, whereas quinolones were inhibitors of the enzyme. This inhibition was compared with that of DNA gyrase and calf thymus topoisomerase I. The 50% inhibitory concentrations for E. coli topoisomerase I were about one order of magnitude higher than the corresponding values for E. coli DNA gyrase but were far lower than the known values for calf thymus topoisomerase I. There was a good relationship between inhibition of the two prokaryotic topoisomerases and MICs for E. coli, and the quinolones could be ranked in the same order in the three cases. Images PMID:2830840

  2. Multi-residue method for the detection of veterinary drugs in distillers grains by liquid chromatography-Orbitrap high resolution mass spectrometry.

    PubMed

    Kaklamanos, George; Vincent, Ursula; von Holst, Christoph

    2013-12-27

    Distillers Grain (DG) is an important by-product of ethanol production. The ethanol production process uses only the starch portion of the plant and all the remaining nutrients, protein, fat, minerals, and vitamins remain in DGs, a valuable feed material for livestock. The use of antimicrobial drugs is helpful to limit harmful bacterial growth during the early part of the fermentation process. This can lead to the possible presence of contaminants in the by-products that are used in the food and feed industries, resulting in a major concern for the development of bacterial resistance in both humans and animals. To facilitate the detection of antimicrobial and other commonly used veterinary drugs in DGs, a liquid chromatography-high resolution mass spectrometry (LC-HRMS) method was developed targeting a wide range of 12 chemical classes of anti-bacterial substances and drugs, such as ionophore and non-ionophore authorized coccidiostats, banned coccidiostats, macrolides, tetracyclines, nitroimidazoles, amphenicols, quinolones, sulphonamides, tranquilizers, non-steroidal anti-inflammatory drugs and benzimidazoles. Following a simple and fast extraction step with a mixture of organic solvents, the extract was directly injected into the LC coupled to an Orbitrap mass analyzer. The identification of residues is based on accurate mass measurement. The high mass resolution of 50,000 full width at half maximum (FWHM) and corresponding narrow mass windows permitted a very selective and sensitive detection of the analytes in such a complex matrix. A single-laboratory validation procedure was carried out evaluating selectivity, sensitivity, linearity, precision and accuracy. The method showed satisfactory analytical performance for precision and trueness, and allowed the determination of the compounds at low concentration. The proposed multi-method demonstrated that liquid chromatography coupled to an Orbitrap mass spectrometer is a promising analytical technique, suitable for official residue control of a variety of veterinary drugs in DGs supporting feed safety policies. PMID:24239439

  3. In Vitro Antianaerobic Activity of DX-619, a New Des-Fluoro(6) Quinolone

    PubMed Central

    Tanaka, Kaori; Mikamo, Hiroshige; Nakao, Ken'ichi; Watanabe, Kunitomo

    2006-01-01

    The in vitro activity of DX-619, a new des-F(6) quinolone, against anaerobic bacteria was evaluated. DX-619 showed potent activity against Bacteroides, Prevotella, Fusobacterium, Micromonas, Actinomyces, and Clostridium spp., with MIC50s/MIC90s of ≤0.03 to 0.25/≤0.03 to 1 μg/ml, respectively. DX-619 was also active against imipenem-resistant Bacteroides spp., with MIC50s/MIC90s of 0.25/1 μg/ml, respectively. PMID:17065629

  4. Lack of efflux mediated quinolone resistance in Salmonella enterica serovars Typhi and Paratyphi A.

    PubMed

    Baucheron, Sylvie; Monchaux, Isabelle; Le Hello, Simon; Weill, François-Xavier; Cloeckaert, Axel

    2014-01-01

    Salmonella enterica serovars Typhi and Paratyphi A isolates from human patients in France displaying different levels of resistance to quinolones or fluoroquinolones were studied for resistance mechanisms to these antimicrobial agents. All resistant isolates carried either single or multiple target gene mutations (i.e., in gyrA, gyrB, or parC) correlating with the resistance levels observed. Active efflux, through upregulation of multipartite efflux systems, has also been previously reported as contributing mechanism for other serovars. Therefore, we investigated also the occurrence of non-target gene mutations in regulatory regions affecting efflux pump expression. However, no mutation was detected in these regions in both Typhi and Paratyphi isolates of this study. Besides, no overexpression of the major efflux systems was observed for these isolates. Nevertheless, a large deletion of 2334 bp was identified in the acrS-acrE region of all S. Typhi strains but which did not affect the resistance phenotype. As being specific to S. Typhi, this deletion could be used for specific molecular detection purposes. In conclusion, the different levels of quinolone or FQ resistance in both S. Typhi and S. Paratyphi A seem to rely only on target modifications. PMID:24478769

  5. Structure Based In Silico Analysis of Quinolone Resistance in Clinical Isolates of Salmonella Typhi from India

    PubMed Central

    Sharma, Priyanka; Sharma, Sujata; Singh, Tej P.; Kapil, Arti; Kaur, Punit

    2015-01-01

    Enteric fever is a major cause of morbidity in several parts of the Indian subcontinent. The treatment for typhoid fever majorly includes the fluoroquinolone group of antibiotics. Excessive and indiscriminate use of these antibiotics has led to development of acquired resistance in the causative organism Salmonella Typhi. The resistance towards fluoroquinolones is associated with mutations in the target gene of DNA Gyrase. We have estimated the Minimum Inhibitory Concentration (MIC) of commonly used fluoroquinolone representatives from three generations, ciprofloxacin, ofloxacin, levofloxacin and moxifloxacin, for 100 clinical isolates of Salmonella Typhi from patients in the Indian subcontinent. The MICs have been found to be in the range of 0.032 to 8 μg/ml. The gene encoding DNA Gyrase was subsequently sequenced and point mutations were observed in DNA Gyrase in the quinolone resistance determining region comprising Ser83Phe/Tyr and Asp87Tyr/Gly. The binding ability of these four fluoroquinolones in the quinolone binding pocket of wild type as well as mutant DNA Gyrase was computationally analyzed by molecular docking to assess their differential binding behaviour. This study has revealed that mutations in DNA Gyrase alter the characteristics of the binding pocket resulting in the loss of crucial molecular interactions and consequently decrease the binding affinity of fluoroquinolones with the target protein. The present study assists in understanding the underlying molecular and structural mechanism for decreased fluoroquinolone susceptibility in clinical isolates as a consequence of mutations in DNA Gyrase. PMID:25962113

  6. Structure based in silico analysis of quinolone resistance in clinical isolates of Salmonella Typhi from India.

    PubMed

    Kumar, Manoj; Dahiya, Sushila; Sharma, Priyanka; Sharma, Sujata; Singh, Tej P; Kapil, Arti; Kaur, Punit

    2015-01-01

    Enteric fever is a major cause of morbidity in several parts of the Indian subcontinent. The treatment for typhoid fever majorly includes the fluoroquinolone group of antibiotics. Excessive and indiscriminate use of these antibiotics has led to development of acquired resistance in the causative organism Salmonella Typhi. The resistance towards fluoroquinolones is associated with mutations in the target gene of DNA Gyrase. We have estimated the Minimum Inhibitory Concentration (MIC) of commonly used fluoroquinolone representatives from three generations, ciprofloxacin, ofloxacin, levofloxacin and moxifloxacin, for 100 clinical isolates of Salmonella Typhi from patients in the Indian subcontinent. The MICs have been found to be in the range of 0.032 to 8 μg/ml. The gene encoding DNA Gyrase was subsequently sequenced and point mutations were observed in DNA Gyrase in the quinolone resistance determining region comprising Ser83Phe/Tyr and Asp87Tyr/Gly. The binding ability of these four fluoroquinolones in the quinolone binding pocket of wild type as well as mutant DNA Gyrase was computationally analyzed by molecular docking to assess their differential binding behaviour. This study has revealed that mutations in DNA Gyrase alter the characteristics of the binding pocket resulting in the loss of crucial molecular interactions and consequently decrease the binding affinity of fluoroquinolones with the target protein. The present study assists in understanding the underlying molecular and structural mechanism for decreased fluoroquinolone susceptibility in clinical isolates as a consequence of mutations in DNA Gyrase. PMID:25962113

  7. Role of the Pseudomonas quinolone signal (PQS) in sensitising Pseudomonas aeruginosa to UVA radiation.

    PubMed

    Pezzoni, Magdalena; Meichtry, Martín; Pizarro, Ramón A; Costa, Cristina S

    2015-01-01

    One of the main stress factors that bacteria face in the environment is solar ultraviolet-A (UVA) radiation, which leads to lethal effects through oxidative damage. The aim of this work was to investigate the role of 2-heptyl-3-hydroxi-4-quinolone (the Pseudomonas quinolone signal or PQS) in the response of Pseudomonas aeruginosa to UVA radiation. PQS is an intercellular quorum sensing signal associated to membrane vesicles which, among other functions, regulates genes related to iron acquisition, forms stable complexes with iron and participates in oxidative phenomena. UVA exposure of the wild-type PAO1 strain and a pqsA mutant unable to produce PQS revealed a sensitising role for this signal. Research into the mechanism involved in this phenomenon revealed that catalase, an essential factor in the UVA defence, is not related to PQS-mediated UVA sensitivity. Absorption of UVA by PQS produced its own photo-degradation, oxidation of the probe 2',7'- dichlorodihydrofluorescein and generation of singlet oxygen and superoxide anion, suggesting that this signal could be acting as an endogenous photosensitiser. The results presented in this study could explain the high sensitivity to UVA of P. aeruginosa when compared to enteric bacteria. PMID:25535873

  8. [The sensitivity of Salmonella strains in diarrheal disease to new quinolones compared with other antimicrobial substances].

    PubMed

    David, E; Andronescu, D; Serban, D; Cocean, S

    1996-01-01

    The sensitivity of 59 Salmonella strains isolated in children with acute diarrhoea was tested against the new quinolones like: Ciproflaxicin (CIP), Norfloxacin (NOR) and Ofloxacin (OFX), as compared to the sensitivity against same aminosides: Gentamicin (GM), Amikacin (AN) against cephalosporins: Ceftazidime (CAZ), Cefalotine (CF) and other currently used antimicrobial agents: Tetraciclin (T), Ampicilin (A), Cloramfenicol (C), Furazolidon (FU). The majority of the studied Salmonella strains, 43 out of 59 strains, belonged to the serotype typhimurium, the most frequently serotype isolated in our geographical area. A very high percentage of Salmonella strains were sensitive against the three quinolones: 98,30% sensitive against NOR, 91,5% sensitive against OFX, 91,50% sensitive against CIP and 96,6% sensitive against AN. In contrast, the Salmonella strains sensitivity was lower in the other tested antimicrobial substances: C (32,2% sensitive strains), GM (8,5%), A (16,9%), CF (11,9%), T (3,4%), FU (1,7%). Out of 59 strains, 45 where resistant to more than four antibiotics, the most often observed pattern was: A, CAZ, CF, GM, T, C, FU. PMID:8963116

  9. Antibiotics Threaten Wildlife: Circulating Quinolone Residues and Disease in Avian Scavengers

    PubMed Central

    Lemus, Jesús Á.; Blanco, Guillermo; Grande, Javier; Arroyo, Bernardo; García-Montijano, Marino; Martínez, Felíx

    2008-01-01

    Antibiotic residues that may be present in carcasses of medicated livestock could pass to and greatly reduce scavenger wildlife populations. We surveyed residues of the quinolones enrofloxacin and its metabolite ciprofloxacin and other antibiotics (amoxicillin and oxytetracycline) in nestling griffon Gyps fulvus, cinereous Aegypius monachus and Egyptian Neophron percnopterus vultures in central Spain. We found high concentrations of antibiotics in the plasma of many nestling cinereous (57%) and Egyptian (40%) vultures. Enrofloxacin and ciprofloxacin were also found in liver samples of all dead cinereous vultures. This is the first report of antibiotic residues in wildlife. We also provide evidence of a direct association between antibiotic residues, primarily quinolones, and severe disease due to bacterial and fungal pathogens. Our results indicate that, by damaging the liver and kidney and through the acquisition and proliferation of pathogens associated with the depletion of lymphoid organs, continuous exposure to antibiotics could increase mortality rates, at least in cinereous vultures. If antibiotics ingested with livestock carrion are clearly implicated in the decline of the vultures in central Spain then it should be considered a primary concern for conservation of their populations. PMID:18197254

  10. Dueling quorum sensing systems in Pseudomonas aeruginosa control the production of the Pseudomonas quinolone signal (PQS).

    PubMed

    McGrath, Stephen; Wade, Dana S; Pesci, Everett C

    2004-01-15

    The opportunistic human pathogen Pseudomonas aeruginosa regulates the production of numerous virulence factors via the action of two separate but coordinated quorum sensing systems, las and rhl. These systems control the transcription of genes in response to population density through the intercellular signals N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C(12)-HSL) and N-(butanoyl)-L-homoserine lactone (C(4)-HSL). A third P. aeruginosa signal, 2-heptyl-3-hydroxy-4-quinolone [Pseudomonas quinolone signal (PQS)], also plays a significant role in the transcription of multiple P. aeruginosa virulence genes. PQS is intertwined in the P. aeruginosa quorum sensing hierarchy with its production and bioactivity requiring the las and rhl quorum sensing systems, respectively. This report presents a preliminary transcriptional analysis of pqsA, the first gene of the recently discovered PQS biosynthetic gene cluster. We show that pqsA transcription required pqsR, a transcriptional activator protein encoded within the PQS biosynthetic gene cluster. It was also found that the transcription of pqsA and subsequent production of PQS was induced by the las quorum sensing system and repressed by the rhl quorum sensing system. In addition, PQS production was dependent on the ratio of 3-oxo-C(12)-HSL to C(4)-HSL, suggesting a regulatory balance between quorum sensing systems. These data are an important early step toward understanding the regulation of PQS synthesis and the role of PQS in P. aeruginosa intercellular signaling. PMID:14734162

  11. Development and evaluation of a multiplex PCR for eight plasmid-mediated quinolone-resistance determinants.

    PubMed

    Ciesielczuk, H; Hornsey, M; Choi, V; Woodford, N; Wareham, D W

    2013-12-01

    The objective of this study was to develop and validate an expanded multiplex PCR assay for the simultaneous detection of eight plasmid-mediated quinolone-resistance determinants in Enterobacteriaceae. Primers were designed to amplify conserved fragments of qnrABCDS, qepA, oqxAB and aac(6')-Ib-cr genes and were optimized in uniplex and multiplex PCR assays with control template DNA. The assay was used to determine the prevalence of plasmid-mediated quinolone resistance (PMQR) genes in 174 ciprofloxacin-resistant and 43 ciprofloxacin-susceptible extraintestinal pathogenic Escherichia coli isolates. Each resistance gene could be detected alone and in combination. PMQR determinants were detected in 65 ciprofloxacin-resistant isolates (37 %) and one ciprofloxacin-susceptible isolate (2 %). Prevalences of the identified determinants were: aac(6')-Ib-cr, 34.5 %; qnrS, 1.1 %; qepA, 1.1 %; and oqxAB, 0.6 %. In conclusion, we developed an eight-target multiplex PCR for the accurate detection of PMQR genes and confirmed that PMQR prevalence remains low among human Escherichia coli clinical isolates in the UK. PMID:24000223

  12. [Antibacterial therapy for acute cystitis in the age of growing pathogen resistance].

    PubMed

    Siniakova, L A

    2014-01-01

    Acute cystitis refers to uncomplicated lower urinary tract infections, with the recurrence rates after the first cystitis episode being 50%. The basic treatment for the above diseases is antibacterial therapy, whose efficiency depends entirely on the right choice of a drug during initial empiric therapy. The paper gives the European Association of Urology guidelines and Russian guidelines, which are based on the results of both international (ARESC) and Russian (DARMIS) studies of urinary tract infection pathogens and their susceptibility to antibacterial drugs. Phosphomycin trometamol and furasidine potassium are the drugs of choice to treat acute cystitis in Russia now. PMID:24864480

  13. Shifts in the Antibiotic Susceptibility, Serogroups, and Clonal Complexes of Neisseria meningitidis in Shanghai, China: A Time Trend Analysis of the Pre-Quinolone and Quinolone Eras

    PubMed Central

    Wang, Ye; Zou, Ying; Wang, Gangyi; Zhang, Xi; Xu, Xiaogang; Zhao, Miao; Hu, Fupin; Qu, Di; Chen, Min; Wang, Minggui

    2015-01-01

    Background Fluoroquinolones have been used broadly since the end of the 1980s and have been recommended for Neisseria meningitidis prophylaxis since 2005 in China. The aim of this study was to determine whether and how N. meningitidis antimicrobial susceptibility, serogroup prevalence, and clonal complex (CC) prevalence shifted in association with the introduction and expanding use of quinolones in Shanghai, a region with a traditionally high incidence of invasive disease due to N. meningitidis. Methods and Findings A total of 374 N. meningitidis isolates collected by the Shanghai Municipal Center for Disease Control and Prevention between 1965 and 2013 were studied. Shifts in the serogroups and CCs were observed, from predominantly serogroup A CC5 (84%) in 1965–1973 to serogroup A CC1 (58%) in 1974–1985, then to serogroup C or B CC4821 (62%) in 2005–2013. The rates of ciprofloxacin nonsusceptibility in N. meningitidis disease isolates increased from 0% in 1965–1985 to 84% (31/37) in 2005–2013 (p < 0.001). Among the ciprofloxacin-nonsusceptible isolates, 87% (27/31) were assigned to either CC4821 (n = 20) or CC5 (n = 7). The two predominant ciprofloxacin-resistant clones were designated ChinaCC4821-R1-C/B and ChinaCC5-R14-A. The ChinaCC4821-R1-C/B clone acquired ciprofloxacin resistance by a point mutation, and was present in 52% (16/31) of the ciprofloxacin-nonsusceptible disease isolates. The ChinaCC5-R14-A clone acquired ciprofloxacin resistance by horizontal gene transfer, and was found in 23% (7/31) of the ciprofloxacin-nonsusceptible disease isolates. The ciprofloxacin nonsusceptibility rate was 47% (7/15) among isolates from asymptomatic carriers, and nonsusceptibility was associated with diverse multi-locus sequence typing profiles and pulsed-field gel electrophoresis patterns. As detected after 2005, ciprofloxacin-nonsusceptible strains were shared between some of the patients and their close contacts. A limitation of this study is that isolates from 1986–2004 were not available and that only a small sample of convenience isolates from 1965–1985 were available. Conclusions The increasing prevalence of ciprofloxacin resistance since 2005 in Shanghai was associated with the spread of hypervirulent lineages CC4821 and CC5. Two resistant meningococcal clones ChinaCC4821-R1-C/B and ChinaCC5-R14-A have emerged in Shanghai during the quinolone era. Ciprofloxacin should be utilized with caution for the chemoprophylaxis of N. meningitidis in China. PMID:26057853

  14. Characterization of Mutations in DNA Gyrase and Topoisomerase IV Involved in Quinolone Resistance of Mycoplasma gallisepticum Mutants Obtained In Vitro

    PubMed Central

    Reinhardt, A. K.; Bbar, C. M.; Kobisch, M.; Kempf, I.; Gautier-Bouchardon, A. V.

    2002-01-01

    Mycoplasma gallisepticum enrofloxacin-resistant mutants were generated by stepwise selection in increasing concentrations of enrofloxacin. Alterations were found in the quinolone resistance-determining regions of the four target genes encoding DNA gyrase and topoisomerase IV from these mutants. This is the first description of such mutations in an animal mycoplasma species. PMID:11796386

  15. INCREASED RECOVERY OF FECAL QUINOLONE-RESISTANT ESCHERICHIA COLI IN CHILDREN USING A MACCONKEY-NALIDIXIC ACID SCREENING PLATE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Commensal bacteria may serve as reservoirs of antibiotic resistance genes. The possibility that these may be transferred to zoonotic pathogens is under study. Resistance to Quinolones is of particular interest because of their value in treating severe human infections. Methods: Plain M...

  16. Assessment of the effectiveness of silver-coated dressing, chlorhexidine acetate (0.5%), citric acid (3%), and silver sulfadiazine (1%) for topical antibacterial effects against the multi-drug resistant Pseudomonas aeruginosa infecting full-skin thickness burn wounds on rats.

    PubMed

    Yabanoglu, Hakan; Basaran, Ozgur; Aydogan, Cem; Azap, Ozlem Kurt; Karakayali, Feza; Moray, Gokhan

    2013-01-01

    The aim of this study was to compare the effects of four different topical antimicrobial dressings on a multi-drug resistant Pseudomonas aeruginosa contaminated full-thickness burn wound rat model. A total of 40 adult male Wistar albino rats were used. The control group (group 1), silver sulfadiazine (1%) group 2, chlorhexidine acetate (0.5%) group 3, citric acid (3%) group 4, and silver-coated dressing group 5 were compared to assess the antibacterial effects of a daily application to a 30% full-skin thickness burn wound seeded 10 minutes earlier with 10(8) CFU (colony forming unit)/0.5 mL of a multi-drug resistant Pseudomonas aeruginosa strain. Five groups (1 control group and 4 treatment groups) were compared. The administration of third-degree burns to all rats was confirmed based on histopathologic data. The tissue cultures from groups 2 and 5 exhibited significant differences compared to those of the other 3 groups, whereas no significant differences were observed between groups 1, 3, and 4. The effectiveness of the treatments was as follows: 1% silver sulfadiazine > silver-coated dressing > 3% citric acid > 0.5% chlorhexidine acetate > control group. Our results supported the efficacy of topical therapy by silver sulfadiazine and silver-coated dressing on infections caused by multi-drug resistant Pseudomonas spp. PMID:24229034

  17. Antibacterial activity of doxycycline-loaded nanoparticles.

    PubMed

    Misra, Ranjita; Sahoo, Sanjeeb K

    2012-01-01

    Doxycycline is a tetracycline antibiotic with a potent antibacterial activity against a wide variety of bacteria. However, poor cellular penetration limits its use for the treatment of infectious disease caused by intracellular pathogens. One potential strategy to overcome this problem is the use of nanotechnology that can help to easily target the intracellular sites of infection. The antibacterial activity of these antibiotics is enhanced by encapsulating it in polymeric nanoparticles. In this study, we describe the improvement of the entrapment efficiency of doxycycline hydrochloride (doxycycline)-loaded PLGA:PCL nanoparticles up to 70% with variation of different formulation parameters such as polymer ratio, amount of drug loading (w/w), solvent selection, electrolyte addition, and pH alteration in the formulation. We have evaluated the efficacy of these nanoparticles over native doxycycline against a strain of Escherichia coli (DH5α) through growth inhibition and colony counting. The results indicate that doxycycline-loaded nanoparticles have superior effectiveness compared to native doxycycline against the above bacterial strain, resulting from the sustained release of doxycycline from nanoparticles. These results are encouraging for the use of these doxycycline-loaded nanoparticles for the treatment of infections caused by doxycycline-sensitive bacteria. PMID:22568901

  18. ESKAPEing the labyrinth of antibacterial discovery.

    PubMed

    Tommasi, Ruben; Brown, Dean G; Walkup, Grant K; Manchester, John I; Miller, Alita A

    2015-08-01

    Antimicrobial drug resistance is a growing threat to global public health. Multidrug resistance among the 'ESKAPE' organisms - encompassing Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. - is of particular concern because they are responsible for many serious infections in hospitals. Although some promising agents are in the pipeline, there is an urgent need for new antibiotic scaffolds. However, antibacterial researchers have struggled to identify new small molecules with meaningful cellular activity, especially those effective against multidrug-resistant Gram-negative pathogens. This difficulty ultimately stems from an incomplete understanding of efflux systems and compound permeation through bacterial membranes. This Opinion article describes findings from target-based and phenotypic screening efforts carried out at AstraZeneca over the past decade, discusses some of the subsequent chemistry challenges and concludes with a description of new approaches comprising a combination of computational modelling and advanced biological tools which may pave the way towards the discovery of new antibacterial agents. PMID:26139286

  19. Crystallization and preliminary crystal structure analysis of the ligand-binding domain of PqsR (MvfR), the Pseudomonas quinolone signal (PQS) responsive quorum-sensing transcription factor of Pseudomonas aeruginosa

    PubMed Central

    Xu, Ningna; Yu, Shen; Moniot, Sébastien; Weyand, Michael; Blankenfeldt, Wulf

    2012-01-01

    The opportunistic bacterial pathogen Pseudomonas aeruginosa employs three transcriptional regulators, LasR, RhlR and PqsR, to control the transcription of a large subset of its genes in a cell-density-dependent process known as quorum sensing. Here, the recombinant production, crystallization and structure solution of the ligand-binding domain of PqsR (MvfR), the LysR-type transcription factor that responds to the Pseudomonas quinolone signal (PQS), a quinolone-based quorum-sensing signal that is unique to P. aeruginosa and possibly a small number of other bacteria, is reported. PqsR regulates the expression of many virulence genes and may therefore be an interesting drug target. The ligand-binding domain (residues 91–319) was produced as a fusion with SUMO, and hexagonal-shaped crystals of purified PqsR_91–319 were obtained using the vapour-diffusion method. Crystallization in the presence of a PQS precursor allowed data collection to 3.25 Å resolution on a synchrotron beamline, and initial phases have been obtained using single-wavelength anomalous diffraction data from seleno-l-methionine-labelled crystals, revealing the space group to be P6522, with unit-cell parameters a = b = 116–120, c = 115–117 Å. PMID:22949189

  20. Crystallization and preliminary crystal structure analysis of the ligand-binding domain of PqsR (MvfR), the Pseudomonas quinolone signal (PQS) responsive quorum-sensing transcription factor of Pseudomonas aeruginosa.

    PubMed

    Xu, Ningna; Yu, Shen; Moniot, Sébastien; Weyand, Michael; Blankenfeldt, Wulf

    2012-09-01

    The opportunistic bacterial pathogen Pseudomonas aeruginosa employs three transcriptional regulators, LasR, RhlR and PqsR, to control the transcription of a large subset of its genes in a cell-density-dependent process known as quorum sensing. Here, the recombinant production, crystallization and structure solution of the ligand-binding domain of PqsR (MvfR), the LysR-type transcription factor that responds to the Pseudomonas quinolone signal (PQS), a quinolone-based quorum-sensing signal that is unique to P. aeruginosa and possibly a small number of other bacteria, is reported. PqsR regulates the expression of many virulence genes and may therefore be an interesting drug target. The ligand-binding domain (residues 91-319) was produced as a fusion with SUMO, and hexagonal-shaped crystals of purified PqsR_91-319 were obtained using the vapour-diffusion method. Crystallization in the presence of a PQS precursor allowed data collection to 3.25 Å resolution on a synchrotron beamline, and initial phases have been obtained using single-wavelength anomalous diffraction data from seleno-L-methionine-labelled crystals, revealing the space group to be P6(5)22, with unit-cell parameters a = b = 116-120, c = 115-117 Å. PMID:22949189

  1. Dual Mode Antibacterial Activity of Ion Substituted Calcium Phosphate Nanocarriers for Bone Infections

    PubMed Central

    Sampath Kumar, T. S.; Madhumathi, K.; Rubaiya, Y.; Doble, Mukesh

    2015-01-01

    Nanotechnology has tremendous potential for the management of infectious diseases caused by multi-drug resistant bacteria, through the development of newer antibacterial materials and efficient modes of antibiotic delivery. Calcium phosphate (CaP) bioceramics are commonly used as bone substitutes due to their similarity to bone mineral and are widely researched upon for the treatment of bone infections associated with bone loss. CaPs can be used as local antibiotic delivery agents for bone infections and can be substituted with antibacterial ions in their crystal structure to have a wide spectrum, sustained antibacterial activity even against drug resistant bacteria. In the present work, a dual mode antibiotic delivery system with antibacterial ion substituted calcium deficient hydroxyapatite (CDHA) nanoparticles has been developed. Antibacterial ions such as zinc, silver, and strontium have been incorporated into CDHA at concentrations of 6, 0.25–0.75, and 2.5–7.5 at. %, respectively. The samples were found to be phase pure, acicular nanoparticles of length 40–50 nm and width 5–6 nm approximately. The loading and release profile of doxycycline, a commonly used antibiotic, was studied from the nanocarriers. The drug release was studied for 5 days and the release profile was influenced by the ion concentrations. The release of antibacterial ions was studied over a period of 21 days. The ion substituted CDHA samples were tested for antibacterial efficacy on Staphylococcus aureus and Escherichia coli by MIC/MBC studies and time-kill assay. AgCDHA and ZnCDHA showed high antibacterial activity against both bacteria, while SrCDHA was weakly active against S. aureus. Present study shows that the antibiotic release can provide the initial high antibacterial activity, and the sustained ion release can provide a long-term antibacterial activity. Such dual mode antibiotic and antibacterial ion release offers an efficient and potent way to treat an incumbent drug resistant infection. PMID:25984512

  2. Characterization of Vibrio fluvialis qnrVC5 Gene in Native and Heterologous Hosts: Synergy of qnrVC5 with other Determinants in Conferring Quinolone Resistance

    PubMed Central

    Vinothkumar, Kittappa; Kumar, G. N.; Bhardwaj, Ashima K.

    2016-01-01

    Resistance of various pathogens toward quinolones has emerged as a serious threat to combat infections. Analysis of plethora of genes and resistance mechanisms associated with quinolone resistance reveals chromosome-borne and transferable determinants. qnr genes have been found to be responsible for transferable quinolone resistance. In the present work, a new allele qnrVC5 earlier reported in Vibrio fluvialis from this laboratory was characterized in detail for its sequence, genetic context and propensity to decrease the susceptibility for quinolones. The study has revealed persistence of qnrVC5 in clinical isolates of V. fluvialis from Kolkata region through the years 2002–2006. qnrVC5 existed in the form of a gene cassette with the open reading frame being flanked by an upstream promoter and a downstream V. cholerae repeat region suggestive of its superintegron origin. Sequence analysis of different qnrVC alleles showed that qnrVC5 was closely related to qnrVC2 and qnrVC4 and these alleles were associated with V. cholerae repeats. In contrast, qnrVC1, qnrVC3, and qnrVC6 belonging to another group were associated with V. parahaemolyticus repeats. The gene manifested its activity in native V. fluvialis host as well as in Escherichia coli transformants harboring it by elevating the MIC toward various quinolones by twofold to eightfold. In combination with other quinolone resistance factors such as topoisomerase mutations and aac(6’)-Ib-cr gene, qnrVC5 gene product contributed toward higher quinolone resistance displayed by V. fluvialis isolates. Silencing of the gene using antisense peptide nucleic acid sensitized the V. fluvialis parent isolates toward ciprofloxacin. Recombinant QnrVC5 vividly demonstrated its role in conferring quinolone resistance. qnrVC5 gene, its synergistic effect and global dissemination should be perceived as a menace for quinolone-based therapies. PMID:26913027

  3. A function of SmeDEF, the major quinolone resistance determinant of Stenotrophomonas maltophilia, is the colonization of plant roots.

    PubMed

    García-León, Guillermo; Hernández, Alvaro; Hernando-Amado, Sara; Alavi, Peyman; Berg, Gabriele; Martínez, José Luis

    2014-08-01

    Quinolones are synthetic antibiotics, and the main cause of resistance to these antimicrobials is mutation of the genes encoding their targets. However, in contrast to the case for other organisms, such mutations have not been found in quinolone-resistant Stenotrophomonas maltophilia isolates, in which overproduction of the SmeDEF efflux pump is a major cause of quinolone resistance. SmeDEF is chromosomally encoded and highly conserved in all studied S. maltophilia strains; it is an ancient element that evolved over millions of years in this species. It thus seems unlikely that its main function would be resistance to quinolones, a family of synthetic antibiotics not present in natural environments until the last few decades. Expression of SmeDEF is tightly controlled by the transcriptional repressor SmeT. Our work shows that plant-produced flavonoids can bind to SmeT, releasing it from smeDEF and smeT operators. Antibiotics extruded by SmeDEF do not impede the binding of SmeT to DNA. The fact that plant-produced flavonoids specifically induce smeDEF expression indicates that they are bona fide effectors regulating expression of this resistance determinant. Expression of efflux pumps is usually downregulated unless their activity is needed. Since smeDEF expression is triggered by plant-produced flavonoids, we reasoned that this efflux pump may have a role in the colonization of plants by S. maltophilia. Our results showed that, indeed, deletion of smeE impairs S. maltophilia colonization of plant roots. Altogether, our results indicate that quinolone resistance is a recent function of SmeDEF and that colonization of plant roots is likely one original function of this efflux pump. PMID:24837376

  4. A Function of SmeDEF, the Major Quinolone Resistance Determinant of Stenotrophomonas maltophilia, Is the Colonization of Plant Roots

    PubMed Central

    García-León, Guillermo; Hernández, Alvaro; Hernando-Amado, Sara; Alavi, Peyman; Berg, Gabriele

    2014-01-01

    Quinolones are synthetic antibiotics, and the main cause of resistance to these antimicrobials is mutation of the genes encoding their targets. However, in contrast to the case for other organisms, such mutations have not been found in quinolone-resistant Stenotrophomonas maltophilia isolates, in which overproduction of the SmeDEF efflux pump is a major cause of quinolone resistance. SmeDEF is chromosomally encoded and highly conserved in all studied S. maltophilia strains; it is an ancient element that evolved over millions of years in this species. It thus seems unlikely that its main function would be resistance to quinolones, a family of synthetic antibiotics not present in natural environments until the last few decades. Expression of SmeDEF is tightly controlled by the transcriptional repressor SmeT. Our work shows that plant-produced flavonoids can bind to SmeT, releasing it from smeDEF and smeT operators. Antibiotics extruded by SmeDEF do not impede the binding of SmeT to DNA. The fact that plant-produced flavonoids specifically induce smeDEF expression indicates that they are bona fide effectors regulating expression of this resistance determinant. Expression of efflux pumps is usually downregulated unless their activity is needed. Since smeDEF expression is triggered by plant-produced flavonoids, we reasoned that this efflux pump may have a role in the colonization of plants by S. maltophilia. Our results showed that, indeed, deletion of smeE impairs S. maltophilia colonization of plant roots. Altogether, our results indicate that quinolone resistance is a recent function of SmeDEF and that colonization of plant roots is likely one original function of this efflux pump. PMID:24837376

  5. Substituted Hydroxyapatites with Antibacterial Properties

    PubMed Central

    Kolmas, Joanna; Groszyk, Ewa; Kwiatkowska-Różycka, Dagmara

    2014-01-01

    Reconstructive surgery is presently struggling with the problem of infections located within implantation biomaterials. Of course, the best antibacterial protection is antibiotic therapy. However, oral antibiotic therapy is sometimes ineffective, while administering an antibiotic at the location of infection is often associated with an unfavourable ratio of dosage efficiency and toxic effect. Thus, the present study aims to find a new factor which may improve antibacterial activity while also presenting low toxicity to the human cells. Such factors are usually implemented along with the implant itself and may be an integral part of it. Many recent studies have focused on inorganic factors, such as metal nanoparticles, salts, and metal oxides. The advantages of inorganic factors include the ease with which they can be combined with ceramic and polymeric biomaterials. The following review focuses on hydroxyapatites substituted with ions with antibacterial properties. It considers materials that have already been applied in regenerative medicine (e.g., hydroxyapatites with silver ions) and those that are only at the preliminary stage of research and which could potentially be used in implantology or dentistry. We present methods for the synthesis of modified apatites and the antibacterial mechanisms of various ions as well as their antibacterial efficiency. PMID:24949423

  6. Time for a change: addressing R&D and commercialization challenges for antibacterials.

    PubMed

    Payne, David J; Miller, Linda Federici; Findlay, David; Anderson, James; Marks, Lynn

    2015-06-01

    The antibacterial therapeutic area has been described as the perfect storm. Resistance is increasing to the point that our hospitals encounter patients infected with untreatable pathogens, the overall industry pipeline is described as dry and most multinational pharmaceutical companies have withdrawn from the area. Major contributing factors to the declining antibacterial industry pipeline include scientific challenges, clinical/regulatory hurdles and low return on investment. This paper examines these challenges and proposes approaches to address them. There is a need for a broader scientific agenda to explore new approaches to discover and develop antibacterial agents. Additionally, ideas of how industry and academia could be better integrated will be presented. While promising progress in the regulatory environment has been made, more streamlined regulatory paths are still required and the solutions will lie in global harmonization and clearly defined guidance. Creating the right incentives for antibacterial research and development is critical and a new commercial model for antibacterial agents will be proposed. One key solution to help resolve both the problem of antimicrobial resistance (AMR) and lack of new drug development are rapid, cost-effective, accurate point of care diagnostics that will transform antibacterial prescribing and enable more cost-effective and efficient antibacterial clinical trials. The challenges of AMR are too great for any one group to resolve and success will require leadership and partnerships among academia, industry and governments globally. PMID:25918443

  7. Evaluation of the Antibacterial Activity of Patchouli Oil

    PubMed Central

    Yang, Xian; Zhang, Xue; Yang, Shui-Ping; Liu, Wei-Qi

    2013-01-01

    In the present study, the antimicrobial tests of patchouli oil were studied by using molecular docking technology and antimicrobial test in vitro. Five biological macromolecule enzymes, required by the bacteria in the process of biosynthesis were selected as target molecules. Five antibiotics benzylpenicillin, sulfadiazine, trimethoprim, rifampicin and ciprofloxacin, which are generally acknowledged as antibacterial drugs, were selected as reference compounds. The 3 three-dimensional (3D) structures of the 5 reference compounds and 26 compounds from patchouli oil were established by using surflex-dock software (8.1). And the 3D structures of five biological macromolecule enzymes derived from Protein Data Bank (PDB). Molecular docking was carried out between the 31 chemical compounds (ligands) and the 5 enzymes (receptors) by using surflex-dock function. Furthermore, the antibacterial effects of 31 chemical compounds were investigated by the scoring function after molecular docking was completed. By comparing the scoring result of 26 compounds in patchouli oil with 5 compared components, we inferred antibacterial activity in about 26 compounds in patchouli oil. On the other hand, six frequently-used pathogenic bacteria were selected for antimicrobial test in vitro, patchouli oil and its two major compounds: (-)-patchouli alcohol and pogostone, which their contents exceeded 60% in patchouli oil samples, were selected antibacterial agents. Minimum inhibitory concentration (MIC) and Minimum bactericidal concentration (MBC) were also determined. Molecular docking technology and antimicrobial test in vitro proved that patchouli oil had strong antimicrobial effects. Particularly, pogostone and (-)-patchouli alcohol have potent antimicrobial activity. PMID:24250637

  8. Synthesis and Antibacterial Activity of Novel Pleuromutilin Derivatives.

    PubMed

    Liu, Huixian; Xiao, Sui; Zhang, Depeng; Mu, Shuhua; Zhang, Lifang; Wang, Xiaoyang; Xue, Feiqun

    2015-01-01

    In this study we describe the design, synthesis, and antibacterial activity of novel pleuromutilin analogs. A series of new compounds containing piperazine and alkylamino or arylamino groups was synthesized. The new compounds were characterized via (1)H-NMR, (13)C-NMR, Fourier transform (FT)-IR and MS, and were further evaluated for their in vitro activity against seven Gram-positive, and one Gram-negative, pathogens. Antibacterial data revealed that all compounds exhibited moderate to good antibacterial activities against sensitive Gram-positive pathogens. Specifically, 9d displayed the best activity: its activity to Staphylococcus aureus (ATCC25923) is 0.125 µg/mL, which is equal to the control compound tiamulin. The antibacterial activities of 9d to Streptococcus suis (minimum inhibitory concentration (MIC) of 2 µg/mL), Streptococcus agalactiae (MIC of 0.5 µg/mL), and Streptococcus dysgalactiae (MIC of 0.5 µg/mL) were also excellent compared with the control drug erythromycin (MIC of >128 µg/mL). The binding modes of these compounds with active sites were calculated using the programs of Molecular Operating Environment (MOE) and Pymol. PMID:26133714

  9. Controlled release and antibacterial activity of tetracycline hydrochloride-loaded bacterial cellulose composite membranes.

    PubMed

    Shao, Wei; Liu, Hui; Wang, Shuxia; Wu, Jimin; Huang, Min; Min, Huihua; Liu, Xiufeng

    2016-07-10

    Bacterial cellulose (BC) is widely used in biomedical applications. In this study, we prepared an antibiotic drug tetracycline hydrochloride (TCH)-loaded bacterial cellulose (BC) composite membranes, and evaluated the drug release, antibacterial activity and biocompatibility. The structure and morphology of the fabricated BC-TCH composite membranes were characterized using scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). The TCH release results show that the incorporation of BC matrix to load TCH is able to control the release. In vitro antibacterial assay demonstrate that the developed BC-TCH composites displayed excellent antibacterial activity solely associated with the loaded TCH drug. More importantly, the BC-TCH composite membranes display good biocompatibility. These characteristics of BC-TCH composite membranes indicate that they may successfully serve as wound dressings and other medical biomaterials. PMID:27106158

  10. [Impact on public health of quinolone resistance in animal-origin bacteria].

    PubMed

    Orden Gutiérrez, J A; de la Fuente López, R

    2001-01-01

    Fluoroquinolones are one of the most useful classes of antimicrobial agents used in human and animal medicine today, both because of their spectrum and their physicochemical properties. The use of quinolones in animals is a matter of special concern because it could contribute to the acquisition of resistance in foodborn bacteria (such as Salmonella spp., Campylobacter spp. and Escherichia coli) and this, in turn, could lead to a reduction in the efficacy of such compounds in treating infections in humans. However, the causal relationship between the use of fluoroquinolones in veterinary medicine and the isolation of fluoroquinolone-resistant bacteria in humans has not been generally proven and, moreover, the use of fluoroquinolones in animals is only one of the many factors implicated in the resistance to these antimicrobials. Even so, the surveillance of fluoroquinolone resistance in bacteria isolated from animals and foods and the prudent use of these antimicrobials in animals should have the highest priority. PMID:11693069

  11. Subinhibitory concentrations of the cationic antimicrobial peptide colistin induce the pseudomonas quinolone signal in Pseudomonas aeruginosa.

    PubMed

    Cummins, Joanne; Reen, F Jerry; Baysse, Christine; Mooij, Marlies J; O'Gara, Fergal

    2009-09-01

    Colistin is an important cationic antimicrobial peptide (CAMP) in the fight against Pseudomonas aeruginosa infection in cystic fibrosis (CF) lungs. The effects of subinhibitory concentrations of colistin on gene expression in P. aeruginosa were investigated by transcriptome and functional genomic approaches. Analysis revealed altered expression of 30 genes representing a variety of pathways associated with virulence and bacterial colonization in chronic infection. These included response to osmotic stress, motility, and biofilm formation, as well as genes associated with LPS modification and quorum sensing (QS). Most striking was the upregulation of Pseudomonas quinolone signal (PQS) biosynthesis genes, including pqsH, pqsB and pqsE, and the phenazine biosynthesis operon. Induction of this central component of the QS network following exposure to subinhibitory concentrations of colistin may represent a switch to a more robust population, with increased fitness in the competitive environment of the CF lung. PMID:19477905

  12. A comparison of the penetration of two quinolones into intra-abdominal abscess.

    PubMed

    Tudor, R G; Youngs, D J; Yoshioka, K; Burdon, D W; Keighley, M R

    1988-12-01

    A low-mortality model of an intra-abdominal abscess in the rat has been used to study the penetration of two quinolone agents into pus. Maximum concentrations in pus after intravenous injections were achieved at four hours (ciprofloxacin: 12.7 +/- 3.69 mg/L, fleroxacin: 2.25 +/- 1.82 mg/L), whereas fleroxacin given orally reached the maximum level at two hours (13.39 +/- 3.13 mg/L). Higher concentrations of fleroxacin were recorded in pus than in serum at each time point up to eight hours after administration, but pus levels of ciprofloxacin only exceeded serum levels after 1.5 hours. These antibiotics appear to have a unique property of high penetration into established abscesses and may have an important therapeutic role in the treatment of patients with multiple interloop abscesses. PMID:3142444

  13. Design, synthesis and antimycobacterial activities of 1-methyl-2-alkenyl-4(1H)-quinolones

    PubMed Central

    Wube, Abraham A.; Hüfner, Antje; Thomaschitz, Christina; Blunder, Martina; Kollroser, Manfred; Bauer, Rudolf; Bucar, Franz

    2011-01-01

    A series of 23 new 1-methyl-2-alkenyl-4(1H)quinolones have been synthesized and evaluated in vitro for their antimycobacterial activities against fast growing species of mycobacteria, such as Mycobacterium fortuitum, M. smegmatis and M. phlei. The compounds displayed good to excellent inhibition of the growth of the mycobacterial test strains with improved antimycobacterial activity compared to the hit compound, evocarpine. The most active compounds, which possessed chain length of 11–13 carbons at position-2 displayed potent inhibitory effects with an MIC value of 1.0 mg/L. In a human diploid embryonic lung cell line, MRC-5 cytotoxicity assay, the alkaloids showed weak to moderate cytotoxic activity. Biological evaluation of these evocarpine analogues on the less pathogenic fast growing strains of mycobacteria showed an interesting antimycobacterial profile and provided significant insight into the structure–activity relationships. PMID:21106378

  14. Quinolone effects in the SOS chromotest and the synthesis of biomacromolecules.

    PubMed

    Majtnov, L; Majtn, V

    1996-01-01

    The genotoxicity of quinolone antibiotics (ciprofloxacin, enoxacin, nalidixic acid, norfloxacin, ofloxacin, pefloxacin) was studied on the selected mutant E. coli strain PQ 37 (SOS chromotest). The genotoxicity was expressed by SOS-inducing potential (SOSIP) values. The highest SOSIP values were found with ciprofloxacin (SOSIP = 1967 delta IF/nmol), the lowest value was observed with nalidixic acid (SOSIP = 0.3 delta IF/nmol). Similar results were also found with the biosynthesis of nucleic acids, as indicated by incorporation of 14C-adenine into TCA-insoluble fractions of S. typhimurium cells (ciprofloxacin IC50 = 0.39, nalidixic acid IC50 = 400). DNA-damaging effects were tested in the absence of an exogenous metabolizing system. PMID:9449772

  15. Antibacterial Biomimetic Hybrid Films

    PubMed Central

    Ferrer, M. Carme Coll; Hickok, Noreen J.; Eckmann, David M.; Composto, Russell J.

    2012-01-01

    In this work, we present a novel method to prepare a hybrid coating based on dextran grafted to a substrate and embedded with silver nanoparticles (Ag NPs). First, the Ag NPs are synthesized in situ in the presence of oxidized dextran in solution. Second, the oxidized dextran is exposed to an amine functionalized surface resulting in the simultaneous grafting of dextran and the trapping of Ag NPs within the layer. The NP loading is controlled by the concentration of silver nitrate, which is 2 mM (DEX-Ag2) and 5 mM (DEX-Ag5). The dried film thickness increases with silver nitrate concentration from 2 nm for dextran to 7 nm and 12 nm for DEX-Ag2 and DEX-Ag5, respectively. The grafted dextran film displays features with a diameter and height of ~ 50 nm and 2 nm, respectively. For the DEX-Ag2 and DEX-Ag5, the dextran features as well as individual Ag NPs (~ 5 nm) and aggregates of Ag NPs are observed. Larger and more irregular aggregates are observed for DEX-Ag5. Overall, the Ag NPs are embedded in the dextran film as suggested by AFM and UVO studies. In terms of its antimicrobial activity, DEX-Ag2 resists bacterial adhesion to a greater extent than DEX-Ag5, which in turn is better than dextran and silicon. Because these antibacterial hybrid coatings can be grafted to a variety of surfaces, many biomedical applications can be envisioned, ranging from coating implants to catheters. PMID:23807896

  16. Complete Proteome of a Quinolone-Resistant Salmonella Typhimurium Phage Type DT104B Clinical Strain

    PubMed Central

    Correia, Susana; Nunes-Miranda, Júlio D.; Pinto, Luís; Santos, Hugo M.; de Toro, María; Sáenz, Yolanda; Torres, Carmen; Capelo, José Luis; Poeta, Patrícia; Igrejas, Gilberto

    2014-01-01

    Salmonellosis is one of the most common and widely distributed foodborne diseases. The emergence of Salmonella strains that are resistant to a variety of antimicrobials is a serious global public health concern. Salmonella enterica serovar Typhimurium definitive phage type 104 (DT104) is one of these emerging epidemic multidrug resistant strains. Here we collate information from the diverse and comprehensive range of experiments on Salmonella proteomes that have been published. We then present a new study of the proteome of the quinolone-resistant Se20 strain (phage type DT104B), recovered after ciprofloxacin treatment and compared it to the proteome of reference strain SL1344. A total of 186 and 219 protein spots were recovered from Se20 and SL1344 protein extracts, respectively, after two-dimensional gel electrophoresis. The signatures of 94% of the protein spots were successfully identified through matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF MS). Three antimicrobial resistance related proteins, whose genes were previously detected by polymerase chain reaction (PCR), were identified in the clinical strain. The presence of these proteins, dihydropteroate synthase type-2 (sul2 gene), aminoglycoside resistance protein A (strA gene) and aminoglycoside 6'-N-acetyltransferase type Ib-cr4 (aac(6')-Ib-cr4 gene), was confirmed in the DT104B clinical strain. The aac(6')-Ib-cr4 gene is responsible for plasmid-mediated aminoglycoside and quinolone resistance. This is a preliminary analysis of the proteome of these two S. Typhimurium strains and further work is being developed to better understand how antimicrobial resistance is developing in this pathogen. PMID:25196519

  17. Influence of the Pseudomonas quinolone signal on denitrification in Pseudomonas aeruginosa.

    PubMed

    Toyofuku, Masanori; Nomura, Nobuhiko; Kuno, Eriko; Tashiro, Yosuke; Nakajima, Toshiaki; Uchiyama, Hiroo

    2008-12-01

    Denitrification is a well-studied respiratory system that is also important in the biogeochemical nitrogen cycle. Environmental signals such as oxygen and N-oxides have been demonstrated to regulate denitrification, though how denitrification is regulated in a bacterial community remains obscure. Pseudomonas aeruginosa is a ubiquitous bacterium that controls numerous genes through cell-to-cell signals. The bacterium possesses at least two N-acyl-L-homoserine lactone (AHL) signals. In our previous study, these quorum-sensing signals controlled denitrification in P. aeruginosa. In addition to the AHL signals, a third cell-to-cell communication signal, 2-heptyl-3-hydroxy-4-quinolone, referred to as the Pseudomonas quinolone signal (PQS), has been characterized. In this study, we examined the effect of PQS on denitrification to obtain more insight into the respiratory regulation in a bacterial community. Denitrification in P. aeruginosa was repressed by PQS, which was partially mediated by PqsR and PqsE. Measuring the denitrifying enzyme activities indicated that nitrite reductase activity was increased by PQS, whereas PQS inhibited nitric oxide reductase and the nitrate-respiratory chain activities. This is the first report to demonstrate that PQS influences enzyme activities, suggesting this effect is not specific to P. aeruginosa. Furthermore, when iron was supplied to the PQS-added medium, denitrifying activity was almost restored, indicating that the iron chelating property of PQS affected denitrification. Thus, our data indicate that PQS regulates denitrification primarily through iron chelation. The PQS effect on denitrification was relevant in a condition where oxygen was limited and denitrification was induced, suggesting its role in controlling denitrification where oxygen is present. PMID:18931133

  18. A Conserved Suppressor Mutation in a Tryptophan Auxotroph Results in Dysregulation of Pseudomonas Quinolone Signal Synthesis

    PubMed Central

    Knoten, Claire A.; Wells, Greg; Coleman, James P.

    2014-01-01

    Pseudomonas aeruginosa is a common nosocomial pathogen that relies on three cell-to-cell signals to regulate multiple virulence factors. The Pseudomonas quinolone signal (PQS; 2-heptyl-3-hydroxy-4-quinolone) is one of these signals, and it is known to be important for P. aeruginosa pathogenesis. PQS is synthesized in a multistep reaction that condenses anthranilate and a fatty acid. In P. aeruginosa, anthranilate is produced via the kynurenine pathway and two separate anthranilate synthases, TrpEG and PhnAB, the latter of which is important for PQS synthesis. Others have previously shown that a P. aeruginosa tryptophan auxotroph could grow on tryptophan-depleted medium with a frequency of 10−5 to 10−6. These revertants produced more pyocyanin and had increased levels of phnA transcript. In this study, we constructed similar tryptophan auxotroph revertants and found that the reversion resulted from a synonymous G-to-A nucleotide mutation within pqsC. This change resulted in increased pyocyanin and decreased PQS, along with an increase in the level of the pqsD, pqsE, and phnAB transcripts. Reporter fusion and reverse transcriptase PCR studies indicated that a novel transcript containing pqsD, pqsE, and phnAB occurs in these revertants, and quantitative real-time PCR experiments suggested that the same transcript appears in the wild-type strain under nutrient-limiting conditions. These results imply that the PQS biosynthetic operon can produce an internal transcript that increases anthranilate production and greatly elevates the expression of the PQS signal response protein PqsE. This suggests a novel mechanism to ensure the production of both anthranilate and PQS-controlled virulence factors. PMID:24748618

  19. Identification and Evolution of Drug Efflux Pump in Clinical Enterobacter aerogenes Strains Isolated in 1995 and 2003

    PubMed Central

    Garnotel, Eric; Nicolas, Pierre; Davin-Régli, Anne; Pagès, Jean-Marie

    2008-01-01

    Background The high mortality impact of infectious diseases will increase due to accelerated evolution of antibiotic resistance in important human pathogens. Development of antibiotic resistance is a evolutionary process inducing the erosion of the effectiveness of our arsenal of antibiotics. Resistance is not necessarily limited to a single class of antibacterial agents but may affect many unrelated compounds; this is termed ‘multidrug resistance’ (MDR). The major mechanism of MDR is the active expulsion of drugs by bacterial pumps; the treatment of Gram negative bacterial infections is compromised due to resistance mechanisms including the expression of efflux pumps that actively expel various usual antibiotics (ß-lactams, quinolones, …). Methodology/Principal Findings Enterobacter aerogenes has emerged among Enterobacteriaceae associated hospital infections during the last twenty years due to its faculty of adaptation to antibiotic stresses. Clinical isolates of E. aerogenes belonging to two strain collections isolated in 1995 and 2003 respectively, were screened to assess the involvement of efflux pumps in antibiotic resistance. Drug susceptibility assays were performed on all bacterial isolates and an efflux pump inhibitor (PAßN) previously characterized allowed to decipher the role of efflux in the resistance. Accumulation of labelled chloramphenicol was monitored in the presence of an energy poison to determine the involvement of active efflux on the antibiotic intracellular concentrations. The presence of the PAßN-susceptible efflux system was also identified in resistant E. aerogenes strains. Conclusions/Significance For the first time a noticeable increase in clinical isolates containing an efflux mechanism susceptible to pump inhibitor is report within an 8 year period. After the emergence of extended spectrum ß-lactamases in E. aerogenes and the recent characterisation of porin mutations in clinical isolates, this study describing an increase in inhibitor-susceptible efflux throws light on a new step in the evolution of mechanism in E. aerogenes. PMID:18787654

  20. Coexistence of blaOXA-23 with armA in quinolone-resistant Acinetobacter baumannii from a Chinese university hospital.

    PubMed

    Shen, Min; Luan, Guangxin; Wang, Yanhong; Chang, Yaowen; Zhang, Chi; Yang, Jingni; Deng, Shanshan; Ling, Baodong; Jia, Xu

    2016-03-01

    A total of 101 Acinetobacter baumannii isolates were collected to determine the mechanisms of quinolone resistance and investigate the occurrence of carbapenem and high-level aminoglycoside resistance genes among quinolone-resistant strains. Among 77 quinolone-resistant A. baumannii harbored mutations of gyrA and parC, 41 isolates, which belonged to European clone II, had resistance to aminoglycosides and carbapenems due to the expression of armA and acquisition of blaOXA-23. Most of sequence type belonged to clonal complex 92. These results suggested hospital dissemination of multidrug-resistant A. baumannii carrying blaOXA-23, armA, and mutations of quinolone resistance-determining regions in western China. PMID:26740313

  1. Extraction of quinolones from milk samples using bentonite/magnetite nanoparticles before determination by high-performance liquid chromatography with fluorimetric detection.

    PubMed

    Jin, Tao; Wu, Hao; Gao, Nannan; Chen, Xiaodan; Lai, Huajie; Zheng, Jinfeng; Du, Liming

    2016-02-01

    In this work, bentonite magnetic nanoparticles synthesized by a typical coprecipitation method were used as the adsorbent for the magnetic solid-phase extraction of six quinolones (ciprofloxacin, difloxacin, enrofloxacin, norfloxacin, sarafloxacin, and lomefloxacin) from milk samples followed by high-performance liquid chromatography with fluorimetric detection. Under the optimized conditions, the linear quantitation range for the six quinolones was 0.3-200 ng/mL, and the correlation coefficients of the calibration curves ranged from 0.9994 to 0.9999. The detection limit of the method was 0.1 ng/mL. Recoveries of quinolones from pure and low-fat spiked milk samples varied from 80.4 to 92.7% and from 81.3 to 93.5%, respectively. These results demonstrated that the proposed method for the determination of six quinolones in milk samples was rapid, reliable, and efficient. PMID:26576704

  2. Controlled Antibiotics Release System through Simple Blended Electrospun Fibers for Sustained Antibacterial Effects.

    PubMed

    Zhang, Zixin; Tang, Jianxiong; Wang, Heran; Xia, Qinghua; Xu, Shanshan; Han, Charles C

    2015-12-01

    Implantation of sustained antibacterial system after abdominal surgery could effectively prevent complicated intra-abdominal infection. In this study, a simple blended electrospun membrane made of poly(D,L-lactic-co-glycolide) (PLGA)/poly(dioxanone) (PDO)/Ciprofloxacin hydrochloride (CiH) could easily result in approximately linear drug release profile and sustained antibacterial activity against both Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). The addition of PDO changed the stack structure of PLGA, which in turn influenced the fiber swelling and created drug diffusion channels. It could be a good candidate for reducing postoperative infection or be associated with other implant to resist biofilm formation. PMID:26596498

  3. [Current methods of determining the sensitivity to antibacterial preparations of anaerobic microorganisms].

    PubMed

    Dronova, O M; Ponomareva, T R

    1985-11-01

    Antibacterial therapy of infections caused by anaerobic bacteria requires consideration of the data on periodical estimation of sensitivity of the main groups of pathogens to antibacterial drugs. The method of serial dilutions in solid nutrient media is the most accurate and handy for estimation of sensitivity of a large number of strains of anaerobic bacteria. The method of elution of a drug from a paper disk into the liquid thioglycol medium is the most applicable for determination of sensitivity of anaerobic pathogens in specific cases in customary laboratories. PMID:4091519

  4. Antimycobacterial and Antibacterial Activity of Allium sativum Bulbs

    PubMed Central

    Viswanathan, V.; Phadatare, A. G.; Mukne, Alka

    2014-01-01

    Tuberculosis is one of the major public health problems faced globally. Resistance of Mycobacterium tuberculosis to antitubercular agents has called for an urgent need to investigate newer drugs to combat tuberculosis. Garlic (Allium sativum) is an edible plant which has generated a lot of curiosity throughout human history as a medicinal plant. Garlic contains sulfur compounds like allicin, ajoene, allylmethyltrisulfide, diallyltrisulfide, diallyldisulphide and others which exhibit various biological properties like antimicrobial, anticancer, antioxidant, immunomodulatory, antiinflammatory, hypoglycemic, and cardiovascular effects. According to various traditional systems of medicine, garlic is one of the established remedies for tuberculosis. The objective of the current study was to investigate in vitro antimycobacterial activity as well as anti-bacterial activity of various extracts rich in specific phytoconstituents from garlic. Preparation of garlic extracts was done based on the chemistry of the constituents and their stability. The estimation of in vitro antimycobacterial activity of different garlic extracts was done using Resazurin microtire plate assay technique whereas activity of garlic oil was evaluated by colony count method. The antibacterial activity of extracts and oil was estimated by zone of inhibition method. Extracts of garlic rich in allicin and ajoene showed appreciable antimycobacterial activity as compared to standard drugs. Garlic oil demonstrated significant antibacterial activity, particularly against methicillin-resistant Staphylococcus aureus. PMID:25035540

  5. Antimycobacterial and Antibacterial Activity of Allium sativum Bulbs.

    PubMed

    Viswanathan, V; Phadatare, A G; Mukne, Alka

    2014-05-01

    Tuberculosis is one of the major public health problems faced globally. Resistance of Mycobacterium tuberculosis to antitubercular agents has called for an urgent need to investigate newer drugs to combat tuberculosis. Garlic (Allium sativum) is an edible plant which has generated a lot of curiosity throughout human history as a medicinal plant. Garlic contains sulfur compounds like allicin, ajoene, allylmethyltrisulfide, diallyltrisulfide, diallyldisulphide and others which exhibit various biological properties like antimicrobial, anticancer, antioxidant, immunomodulatory, antiinflammatory, hypoglycemic, and cardiovascular effects. According to various traditional systems of medicine, garlic is one of the established remedies for tuberculosis. The objective of the current study was to investigate in vitro antimycobacterial activity as well as anti-bacterial activity of various extracts rich in specific phytoconstituents from garlic. Preparation of garlic extracts was done based on the chemistry of the constituents and their stability. The estimation of in vitro antimycobacterial activity of different garlic extracts was done using Resazurin microtire plate assay technique whereas activity of garlic oil was evaluated by colony count method. The antibacterial activity of extracts and oil was estimated by zone of inhibition method. Extracts of garlic rich in allicin and ajoene showed appreciable antimycobacterial activity as compared to standard drugs. Garlic oil demonstrated significant antibacterial activity, particularly against methicillin-resistant Staphylococcus aureus. PMID:25035540

  6. Alarmingly High Segregation Frequencies of Quinolone Resistance Alleles within Human and Animal Microbiomes Are Not Explained by Direct Clinical Antibiotic Exposure

    PubMed Central

    Field, Wesley; Hershberg, Ruth

    2015-01-01

    Antibiotic resistance poses a major threat to human health. It is therefore important to characterize the frequency of resistance within natural bacterial environments. Many studies have focused on characterizing the frequencies with which horizontally acquired resistance genes segregate within natural bacterial populations. Yet, very little is currently understood regarding the frequency of segregation of resistance alleles occurring within the housekeeping targets of antibiotics. We surveyed a large number of metagenomic datasets extracted from a large variety of host-associated and non host-associated environments for such alleles conferring resistance to three groups of broad spectrum antibiotics: streptomycin, rifamycins, and quinolones. We find notable segregation frequencies of resistance alleles occurring within the target genes of each of the three antibiotics, with quinolone resistance alleles being the most frequent and rifamycin resistance alleles being the least frequent. Resistance allele frequencies varied greatly between different phyla and as a function of environment. The frequency of quinolone resistance alleles was especially high within host-associated environments, where it averaged an alarming ∼40%. Within host-associated environments, resistance to quinolones was most often conferred by a specific resistance allele. High frequencies of quinolone resistance alleles were also found within hosts that were not directly treated with antibiotics. Therefore, the high segregation frequency of quinolone resistance alleles occurring within the housekeeping targets of antibiotics in host-associated environments does not seem to be the sole result of clinical antibiotic usage. PMID:26019163

  7. Shikimic acid, a base compound for the formulation of swine/avian flu drug: statistical optimization, fed-batch and scale up studies along with its application as an antibacterial agent.

    PubMed

    Tripathi, P; Rawat, G; Yadav, S; Saxena, R K

    2015-02-01

    The sudden outbreak of swine flu has increased the global demand of shikimic acid which is an industrially interesting compound, as it is used as a key starting material for the synthesis of a neuraminidase inhibitor Tamiflu(®), for the treatment of antiviral infections such as swine flu. Statistical optimization and evaluation of medium components for the production of shikimic acid by Citrobacter freundii is addressed in the present investigation. Plackett-Burman design was applied for the screening of the most significant variables affecting shikimic acid production, where glucose, asparagine, KH2PO4, CaCO3 and agitation rate were the most significant factors. Response surface methodology was also employed to study the interaction among the most significant variables through which shikimic acid production increased to 12.76 g/L. Further, fed-batch studies resulted in the production of 22.32 g/L of shikimic acid. The scalability of the process was also confirmed by running 14 L bioreactor (7.5 L production medium) where 20.12 g/L of shikimic acid was produced. In addition the antibacterial activity of the shikimic acid produced was analysed against four Gram positive and four Gram negative bacteria and it was found to have a greater inhibition effect against the Gram negative bacteria. PMID:25563634

  8. Pyrazinamide drug interacting with Co(III) and Zn(II) metal ions based on 2,2‧-bipyridine and 1,10-phenanthroline ligands: Synthesis, studies and crystal structure, DFT calculations and antibacterial assays

    NASA Astrophysics Data System (ADS)

    Chiniforoshan, Hossein; Radani, Zahra Sadeghian; Tabrizi, Leila; Tavakol, Hossein; Sabzalian, Mohammad R.; Mohammadnezhad, Gholamhossein; Görls, Helmar; Plass, Winfried

    2015-02-01

    Three novel compounds, [Co(PZAH)(bipy)2](ClO4)2 (1), [Zn(PZAH)(bipy)2]ClO4 (2), [Zn(PZAH)(phen)2]ClO4 (3), which PZAH2 = pyrazinamide, bipy = 2,2‧-bipyridine, phen = 1,10-phenanthroline, were synthesized and characterized by elemental analysis, IR, 1H NMR and electronic absorption spectroscopies. The crystal structure of 1 has been determined in an orthorhombic Pbca space group. The binding modes of the ligands in complex 1 were established by means of molecular modeling of the complex, and calculation of their IR and absorption spectra DFT calculations. The calculated FT-IR and UV-Vis data are in good agreement with the experimental results, and confirmed the experimental one. In addition to DFT calculations of the complex 1, natural bond orbital (NBO) was performed to obtain atomic charges. Biological studies also showed the antibacterial activity of complexes 1-3 against Gram-positive and Gram-negative bacterial strains.

  9. Interaction of vanadium (IV) solvates (L) with second-generation fluoroquinolone antibacterial drug ciprofloxacin: Spectroscopic, structure, thermal analyses, kinetics and biological evaluation (L = An, DMF, Py and Et3N)

    NASA Astrophysics Data System (ADS)

    Zordok, Wael A.

    2014-08-01

    The preparation and characterization of the new solid complexes [VO(CIP)2L]SO4ṡnH2O, where L = aniline (An), dimethylformamide (DMF), pyridine (Py) and triethylamine (Et3N) in the reaction of ciprofloxacin (CIP) with VO(SO4)2·2H2O in ethanol. The isolated complexes have been characterized with their melting points, elemental analysis, IR spectroscopy, magnetic properties, conductance measurements, UV-Vis. and 1H NMR spectroscopic methods and thermal analyses. The results supported the formation of the complexes and indicated that ciprofloxacin reacts as a bidentate ligand bound to the vanadium ion through the pyridone oxygen and one carboxylato oxygen. The activation energies, E*; entropies, ΔS*; enthalpies, ΔH*; Gibbs free energies, ΔG*, of the thermal decomposition reactions have been derived from thermo gravimetric (TGA) and differential thermo gravimetric (DTG) curves, using Coats-Redfern and Horowitz-Metzeger methods. The lowest energy model structure of each complex has been proposed by using the density functional theory (DFT) at the B3LYP/CEP-31G level of theory. The ligand and their metal complexes were also evaluated for their antibacterial activity against several bacterial species, such as Bacillus Subtilis (B. Subtilis), Staphylococcus aureus (S. aureus), Nesseria Gonorrhoeae (N. Gonorrhoeae), Pseudomonas aeruginosa (P. aeruginosa) and Escherichia coli (E. coli).

  10. Scaffold-divergent synthesis of ring-fused indoles, quinolines, and quinolones via iodonium-induced reaction cascades.

    PubMed

    Halim, Rosliana; Aurelio, Luigi; Scammells, Peter J; Flynn, Bernard L

    2013-05-17

    N-(2-Iodophenyl)imines A are readily formed from Schiff's base condensation of 2-iodoanilines with carbonyls and ketals. These imines provide useful substrates in scaffold-divergent synthesis through the attachment of an alkyne (Songashira coupling or acyl substitution of a Weinreb amide) followed by an iodonium-induced reaction cascade to give ring-fused indoles B, quinolines C, or quinolones D depending on the reaction conditions employed. PMID:23659428

  11. Evolution and Dissemination of OqxAB-Like Efflux Pumps, an Emerging Quinolone Resistance Determinant among Members of Enterobacteriaceae

    PubMed Central

    Chan, Edward Wai Chi

    2015-01-01

    The OqxAB efflux pump, a plasmid-mediated quinolone resistance (PMQR) determinant, has become increasingly prevalent among members of Enterobacteriaceae over the past decade. To investigate the evolution and dissemination routes of the oqxAB operon, we assessed the prevalence of oqxAB-like elements among various Gram-negative bacterial species and analyzed the genotypic and phenotypic characteristics of organisms harboring such elements. With a comprehensive genotyping approach, a chromosome-based oqxAB operon was detectable in all Klebsiella pneumoniae strains tested, including organisms isolated before the year 1984. Sequence and phylogenetic analyses confirmed that the oqxAB operon in K. pneumoniae isolates was genetically closest to their plasmid-borne counterparts recoverable only from Escherichia coli and Salmonella isolates collected from the year 2003 onward. Chromosomal elements with much lower sequence homology were also found among the Enterobacter spp. but not other Gram-negative species. Contrary to the quinolone resistance phenotypes which were consistently observable among organisms with oqxAB-harboring plasmids, chromosomal oqxAB elements generally did not confer quinolone resistance, except for K. pneumoniae strains, which exhibited a typical oqxAB-mediated phenotype characterized by cross-resistance to olaquindox, chloramphenicol, and the quinolones. Gene expression analysis illustrated that such phenotypes were due to elevated expression of the chromosomal oqxAB operon. Furthermore, transposition of the oqxAB operon from the bacterial chromosome to plasmids was found to result in a >80-fold increase in the level of expression of the OqxAB pump, confirming its status as the first constitutively expressed efflux system located in bacterial mobile elements. PMID:25801572

  12. Evolution and dissemination of OqxAB-like efflux pumps, an emerging quinolone resistance determinant among members of Enterobacteriaceae.

    PubMed

    Wong, Marcus Ho Yin; Chan, Edward Wai Chi; Chen, Sheng

    2015-01-01

    The OqxAB efflux pump, a plasmid-mediated quinolone resistance (PMQR) determinant, has become increasingly prevalent among members of Enterobacteriaceae over the past decade. To investigate the evolution and dissemination routes of the oqxAB operon, we assessed the prevalence of oqxAB-like elements among various Gram-negative bacterial species and analyzed the genotypic and phenotypic characteristics of organisms harboring such elements. With a comprehensive genotyping approach, a chromosome-based oqxAB operon was detectable in all Klebsiella pneumoniae strains tested, including organisms isolated before the year 1984. Sequence and phylogenetic analyses confirmed that the oqxAB operon in K. pneumoniae isolates was genetically closest to their plasmid-borne counterparts recoverable only from Escherichia coli and Salmonella isolates collected from the year 2003 onward. Chromosomal elements with much lower sequence homology were also found among the Enterobacter spp. but not other Gram-negative species. Contrary to the quinolone resistance phenotypes which were consistently observable among organisms with oqxAB-harboring plasmids, chromosomal oqxAB elements generally did not confer quinolone resistance, except for K. pneumoniae strains, which exhibited a typical oqxAB-mediated phenotype characterized by cross-resistance to olaquindox, chloramphenicol, and the quinolones. Gene expression analysis illustrated that such phenotypes were due to elevated expression of the chromosomal oqxAB operon. Furthermore, transposition of the oqxAB operon from the bacterial chromosome to plasmids was found to result in a >80-fold increase in the level of expression of the OqxAB pump, confirming its status as the first constitutively expressed efflux system located in bacterial mobile elements. PMID:25801572

  13. Pharmacokinetics of Sparfloxacin in the Serum and Vitreous Humor of Rabbits: Physicochemical Properties That Regulate Penetration of Quinolone Antimicrobials

    PubMed Central

    Liu, Weiguo; Liu, Qing Feng; Perkins, Ruth; Drusano, George; Louie, Arnold; Madu, Assumpta; Mian, Umar; Mayers, Martin; Miller, Michael H.

    1998-01-01

    We have used a recently described animal model to characterize the ocular pharmacokinetics of sparfloxacin in vitreous humor of uninfected albino rabbits following systemic administration and direct intraocular injection. The relationships of lipophilicity, protein binding, and molecular weight to the penetration and elimination of sparfloxacin were compared to those of ciprofloxacin, fleroxacin, and ofloxacin. To determine whether elimination was active, elimination rates following direct injection with and without probenecid or heat-killed bacteria were compared. Sparfloxacin concentrations were measured in the serum and vitreous humor by a biological assay. Protein binding and lipophilicity were determined, respectively, by ultrafiltration and oil-water partitioning. Pharmacokinetic parameters were characterized with RSTRIP, an iterative, nonlinear, weighted, least-squares-regression program. The relationship between each independent variable and mean quinolone concentration or elimination rate in the vitreous humor was determined by multiple linear regression. The mean concentration of sparfloxacin in the vitreous humor was 59.4% ± 12.2% of that in serum. Penetration of sparfloxacin, ciprofloxacin, fleroxacin, and ofloxacin into, and elimination from, the vitreous humor correlated with lipophilicity (r2 > 0.999). The linear-regression equation describing this relationship was not improved by including the inverse of the square root of the molecular weight and/or the degree of protein binding. Elimination rates for each quinolone were decreased by the intraocular administration of probenecid. Heat-killed Staphylococcus epidermidis decreased the rate of elimination of fleroxacin. Penetration of sparfloxacin into the noninflamed vitreous humor was greater than that of any quinolone previously examined. There was an excellent correlation between lipophilicity and vitreous entry or elimination for sparfloxacin as well as ciprofloxacin, fleroxacin, and ofloxacin. There are two modes of quinolone translocation into and out of the vitreous humor: diffusion into the eye and both diffusion and carrier-mediated elimination out of the vitreous humor. PMID:9624487

  14. Luminescent determination of quinolones in milk samples by liquid chromatography/post-column derivatization with terbium oxide nanoparticles.

    PubMed

    Ynez-Jcome, G S; Aguilar-Caballos, M P; Gmez-Hens, A

    2015-07-31

    The usefulness of terbium oxide nanoparticles (Tb4O7NPs) as post-column derivatizing reagent for the liquid chromatographic determination of residues of quinolone antibiotics in milk samples has been studied. Seven quinolones of veterinary use have been chosen as model analytes to develop this method. The derivatization step is based on the formation of luminescent chelates of quinolones with Tb4O7NPs, which are monitored at ?ex=340nm and ?em=545nm. Another relevant feature of the method is that the use of a 10-cm column and a ternary mixture of methanol, acetonitrile and acetic acid as mobile phase in gradient elution mode allow the chromatographic separation of the quinolones in about 13min, whereas previously described chromatographic methods require about 20min. The dynamic ranges of the calibration graphs and limits of detection are, respectively: 65-900ngmL(-1) and 35ngmL(-1) for marbofloxacin, 7.2-900ngmL(-1) and 2.5ngmL(-1) for ciprofloxacin, 6-900ngmL(-1) and 2ngmL(-1) for danofloxacin, 50-900ngmL(-1) and 20ngmL(-1) for enrofloxacin, 35-900ngmL(-1) and 12ngmL(-1) for sarafloxacin, 5-900ngmL(-1) and 2ngmL(-1) for oxolinic acid, and 7-900ngmL(-1) and 2.5ngmL(-1) for flumequine. The precision, established at two concentration levels of each analyte and expressed as the percentage of the relative standard deviation is in the range of 1.9-8.1% using standards, and of 3.4-10.7% in the presence of milk samples. The method has been satisfactorily applied to the analysis of skimmed, semi-skimmed and whole milk samples, with recoveries ranging from 89.0 to 106.5%. PMID:26077970

  15. Enterobacteriaceae resistant to third-generation cephalosporins and quinolones in fresh culinary herbs imported from Southeast Asia.

    PubMed

    Veldman, Kees; Kant, Arie; Dierikx, Cindy; van Essen-Zandbergen, Alieda; Wit, Ben; Mevius, Dik

    2014-05-01

    Since multidrug resistant bacteria are frequently reported from Southeast Asia, our study focused on the occurrence of ESBL-producing Enterobacteriaceae in fresh imported herbs from Thailand, Vietnam and Malaysia. Samples were collected from fresh culinary herbs imported from Southeast Asia in which ESBL-suspected isolates were obtained by selective culturing. Analysis included identification by MALDI-TOF mass spectrometry, susceptibility testing, XbaI-PFGE, microarray, PCR and sequencing of specific ESBL genes, PCR based replicon typing (PBRT) of plasmids and Southern blot hybridization. In addition, the quinolone resistance genotype was characterized by screening for plasmid mediated quinolone resistance (PMQR) genes and mutations in the quinolone resistance determining region (QRDR) of gyrA and parC. The study encompassed fifty samples of ten batches of culinary herbs (5 samples per batch) comprising nine different herb variants. The herbs originated from Thailand (Water morning glory, Acacia and Betel leaf), Vietnam (Parsley, Asian pennywort, Houttuynia leaf and Mint) and Malaysia (Holy basil and Parsley). By selective culturing 21 cefotaxime resistant Enterobacteriaceae were retrieved. Array analysis revealed 18 isolates with ESBL genes and one isolate with solely non-ESBL beta-lactamase genes. Mutations in the ampC promoter region were determined in two isolates with PCR and sequencing. The isolates were identified as Klebsiella pneumoniae (n=9), Escherichia coli (n=6), Enterobacter cloacae complex (n=5) and Enterobacter spp. (n=1). All isolates tested were multidrug resistant. Variants of CTX-M enzymes were predominantly found followed by SHV enzymes. PMQR genes (including aac(6')-1b-cr, qnrB and qnrS) were also frequently detected. In almost all cases ESBL and quinolone resistance genes were located on the same plasmid. Imported fresh culinary herbs from Southeast Asia are a potential source for contamination of food with multidrug resistant bacteria. Because these herbs are consumed without appropriate heating, transfer to human bacteria cannot be excluded. PMID:24607424

  16. Structure-based design of new DHFR-based antibacterial agents: 7-aryl-2,4-diaminoquinazolines.

    PubMed

    Li, Xiaoming; Hilgers, Mark; Cunningham, Mark; Chen, Zhiyong; Trzoss, Michael; Zhang, Junhu; Kohnen, Lucy; Lam, Thanh; Creighton, Chris; G C, Kedar; Nelson, Kirk; Kwan, Bryan; Stidham, Mark; Brown-Driver, Vickie; Shaw, Karen J; Finn, John

    2011-09-15

    Dihydrofolate reductase (DHFR) inhibitors such as trimethoprim (TMP) have long played a significant role in the treatment of bacterial infections. Not surprisingly, after decades of use there is now bacterial resistance to TMP and therefore a need to develop novel antibacterial agents with expanded spectrum including these resistant strains. In this study, we investigated the optimization of 2,4-diamnoquinazolines for antibacterial potency and selectivity. Using structure-based drug design, several 7-aryl-2,4-diaminoquinazolines were discovered that have excellent sub-100 picomolar potency against bacterial DHFR. These compounds have good antibacterial activity especially on gram-positive pathogens including TMP-resistant strains. PMID:21831637

  17. Source Attribution of Human Campylobacter Isolates by MLST and Fla-Typing and Association of Genotypes with Quinolone Resistance

    PubMed Central

    Kittl, Sonja; Heckel, Gerald; Korczak, Bożena M.; Kuhnert, Peter

    2013-01-01

    Campylobacteriosis is the most frequent zoonosis in developed countries and various domestic animals can function as reservoir for the main pathogens Campylobacter jejuni and Campylobacter coli. In the present study we compared population structures of 730 C. jejuni and C. coli from human cases, 610 chicken, 159 dog, 360 pig and 23 cattle isolates collected between 2001 and 2012 in Switzerland. All isolates had been typed with multi locus sequence typing (MLST) and flaB-typing and their genotypic resistance to quinolones was determined. We used complementary approaches by testing for differences between isolates from different hosts with the proportion similarity as well as the fixation index and by attributing the source of the human isolates with Bayesian assignment using the software STRUCTURE. Analyses were done with MLST and flaB data in parallel and both typing methods were tested for associations of genotypes with quinolone resistance. Results obtained with MLST and flaB data corresponded remarkably well, both indicating chickens as the main source for human infection for both Campylobacter species. Based on MLST, 70.9% of the human cases were attributed to chickens, 19.3% to cattle, 8.6% to dogs and 1.2% to pigs. Furthermore we found a host independent association between sequence type (ST) and quinolone resistance. The most notable were ST-45, all isolates of which were susceptible, while for ST-464 all were resistant. PMID:24244747

  18. High resolution melting analysis for rapid mutation screening in gyrase and Topoisomerase IV genes in quinolone-resistant Salmonella enterica.

    PubMed

    Ngoi, Soo Tein; Thong, Kwai Lin

    2014-01-01

    The increased Salmonella resistance to quinolones and fluoroquinolones is a public health concern in the Southeast Asian region. The objective of this study is to develop a high resolution melt curve (HRM) assay to rapidly screen for mutations in quinolone-resistant determining region (QRDR) of gyrase and topoisomerase IV genes. DNA sequencing was performed on 62 Salmonella strains to identify mutations in the QRDR of gyrA, gyrB, parC, and parE genes. Mutations were detected in QRDR of gyrA (n = 52; S83F, S83Y, S83I, D87G, D87Y, and D87N) and parE (n = 1; M438I). Salmonella strains with mutations within QRDR of gyrA are generally more resistant to nalidixic acid (MIC 16 > 256 μg/mL). Mutations were uncommon within the QRDR of gyrB, parC, and parE genes. In the HRM assay, mutants can be distinguished from the wild-type strains based on the transition of melt curves, which is more prominent when the profiles are displayed in difference plot. In conclusion, HRM analysis allows for rapid screening for mutations at the QRDRs of gyrase and topoisomerase IV genes in Salmonella. This assay markedly reduced the sequencing effort involved in mutational studies of quinolone-resistance genes. PMID:25371903

  19. High Resolution Melting Analysis for Rapid Mutation Screening in Gyrase and Topoisomerase IV Genes in Quinolone-Resistant Salmonella enterica

    PubMed Central

    Thong, Kwai Lin

    2014-01-01

    The increased Salmonella resistance to quinolones and fluoroquinolones is a public health concern in the Southeast Asian region. The objective of this study is to develop a high resolution melt curve (HRM) assay to rapidly screen for mutations in quinolone-resistant determining region (QRDR) of gyrase and topoisomerase IV genes. DNA sequencing was performed on 62 Salmonella strains to identify mutations in the QRDR of gyrA, gyrB, parC, and parE genes. Mutations were detected in QRDR of gyrA (n = 52; S83F, S83Y, S83I, D87G, D87Y, and D87N) and parE (n = 1; M438I). Salmonella strains with mutations within QRDR of gyrA are generally more resistant to nalidixic acid (MIC 16 > 256 μg/mL). Mutations were uncommon within the QRDR of gyrB, parC, and parE genes. In the HRM assay, mutants can be distinguished from the wild-type strains based on the transition of melt curves, which is more prominent when the profiles are displayed in difference plot. In conclusion, HRM analysis allows for rapid screening for mutations at the QRDRs of gyrase and topoisomerase IV genes in Salmonella. This assay markedly reduced the sequencing effort involved in mutational studies of quinolone-resistance genes. PMID:25371903

  20. Antibacterial properties of 3-(phenylsulfonyl)-2-pyrazinecarbonitrile.

    PubMed

    Rajamuthiah, Rajmohan; Jayamani, Elamparithi; Majed, Hiwa; Conery, Annie L; Kim, Wooseong; Kwon, Bumsup; Fuchs, Beth Burgwyn; Kelso, Michael J; Ausubel, Frederick M; Mylonakis, Eleftherios

    2015-11-15

    The emergence of multidrug-resistant bacterial strains has heightened the need for new antimicrobial agents based on novel chemical scaffolds that are able to circumvent current modes of resistance. We recently developed a whole-animal drug-screening methodology in pursuit of this goal and now report the discovery of 3-(phenylsulfonyl)-2-pyrazinecarbonitrile (PSPC) as a novel antibacterial effective against resistant nosocomial pathogens. The minimum inhibitory concentrations (MIC) of PSPC against Staphylococcus aureus and Enterococcus faecium were 4 μg/mL and 8 μg/mL, respectively, whereas the MICs were higher against the Gram-negative bacteria Klebsiella pneumoniae (64 μg/mL), Acinetobacter baumannii (32 μg/mL), Pseudomonas aeruginosa (>64 μg/mL), and Enterobacter spp. (>64 μg/mL). However, co-treatment of PSPC with the efflux pump inhibitor phenylalanine arginyl β-naphthylamide (PAβN) or with sub-inhibitory concentrations of the lipopeptide antibiotic polymyxin B reduced the MICs of PSPC against the Gram-negative strains by >4-fold. A sulfide analog of PSPC (PSPC-1S) showed no antibacterial activity, whereas the sulfoxide analog (PSPC-6S) showed identical activity as PSPC across all strains, confirming structure-dependent activity for PSPC and suggesting a target-based mechanism of action. PSPC displayed dose dependent toxicity to both Caenorhabditis elegans and HEK-293 mammalian cells, culminating with a survival rate of 16% (100 μg/mL) and 8.5% (64 μg/mL), respectively, at the maximum tested concentration. However, PSPC did not result in hemolysis of erythrocytes, even at a concentration of 64 μg/mL. Together these results support PSPC as a new chemotype suitable for further development of new antibiotics against Gram-positive and Gram-negative bacteria. PMID:26459212

  1. Quorum sensing modulates colony morphology through alkyl quinolones in Pseudomonas aeruginosa

    PubMed Central

    2012-01-01

    Background Acyl-homoserine lactone (acyl-HSL) and alkyl quinolone (AQ) based quorum-sensing (QS) systems are important for Pseudomonas aeruginosa virulence and biofilm formation. The effect of QS on biofilm formation is influenced by various genetic and environmental factors. Here, we used a colony biofilm assay to study the effect of the central acyl-HSL QS regulator, LasR, on biofilm formation and structure in the representative clinical P. aeruginosa isolate ZK2870. Results A lasR mutant exhibited wrinkled colony morphology at 37°C in contrast to the smooth colony morphology of the wild-type. Mutational analysis indicated that wrinkling of the lasR mutant is dependent on pel, encoding a biofilm matrix exopolysaccharide. Suppressor mutagenesis and complementation analysis implicated the AQ signaling pathway as the link between las QS and colony morphology. In this pathway, genes pqsA-D are involved in the synthesis of 4-hydroxyalkyl quinolines ("Series A congeners"), which are converted to 3,4-dihydroxyalkyl quinolines ("Series B congeners", including the well-characterized Pseudomonas Quinolone Signal, PQS) by the product of the LasR-dependent pqsH gene. Measurement of AQ in the wild-type, the lasR pqsA::Tn suppressor mutant as well as the defined lasR, pqsH, and lasR pqsH mutants showed a correlation between 4-hydroxyalkyl quinoline levels and the degree of colony wrinkling. Most importantly, the lasR pqsH double mutant displayed wrinkly morphology without producing any 3,4-dihydroxyalkyl quinolines. Constitutive expression of pqsA-D genes in a lasR pqsR::Tnmutant showed that colony wrinkling does not require the AQ receptor PqsR. Conclusions Taken together, these results indicate that the las QS system represses Pel and modulates colony morphology through a 4-hydroxyalkyl quinoline in a PqsR-independent manner, ascribing a novel function to an AQ other than PQS in P. aeruginosa. PMID:22404951

  2. Oxabicyclooctane-Linked Novel Bacterial Topoisomerase Inhibitors as Broad Spectrum Antibacterial Agents

    PubMed Central

    2014-01-01

    Bacterial resistance is eroding the clinical utility of existing antibiotics necessitating the discovery of new agents. Bacterial type II topoisomerase is a clinically validated, highly effective, and proven drug target. This target is amenable to inhibition by diverse classes of inhibitors with alternative and distinct binding sites to quinolone antibiotics, thus enabling the development of agents that lack cross-resistance to quinolones. Described here are novel bacterial topoisomerase inhibitors (NBTIs), which are a new class of gyrase and topo IV inhibitors and consist of three distinct structural moieties. The substitution of the linker moiety led to discovery of potent broad-spectrum NBTIs with reduced off-target activity (hERG IC50 > 18 μM) and improved physical properties. AM8191 is bactericidal and selectively inhibits DNA synthesis and Staphylococcus aureus gyrase (IC50 = 1.02 μM) and topo IV (IC50 = 10.4 μM). AM8191 showed parenteral and oral efficacy (ED50) at less than 2.5 mg/kg doses in a S. aureus murine infection model. A cocrystal structure of AM8191 bound to S. aureus DNA-gyrase showed binding interactions similar to that reported for GSK299423, displaying a key contact of Asp83 with the basic amine at position-7 of the linker. PMID:24900889

  3. Graphene oxide-based antibacterial cotton fabrics.

    PubMed

    Zhao, Jinming; Deng, Bo; Lv, Min; Li, Jingye; Zhang, Yujie; Jiang, Haiqing; Peng, Cheng; Li, Jiang; Shi, Jiye; Huang, Qing; Fan, Chunhai

    2013-09-01

    Graphene oxide (GO) is an excellent bacteria-killing nanomaterial. In this work, macroscopic applications of this promising nanomaterial by fixing GO sheets onto cotton fabrics, which possess strong antibacterial property and great laundering durability, are reported. The GO-based antibacterial cotton fabrics are prepared in three ways: direct adsorption, radiation-induced crosslinking, and chemical crosslinking. Antibacterial tests show that all these GO-containing fabrics possess strong antibacterial property and could inactivate 98% of bacteria. Most significantly, these fabrics can still kill >90% bacteria even after being washed for 100 times. Also importantly, animal tests show that GO-modified cotton fabrics cause no irritation to rabbit skin. Hence, it is believed that these flexible, foldable, and re-usable GO-based antibacterial cotton fabrics have high promise as a type of new nano-engineered antibacterial materials for a wide range of applications. PMID:23483725

  4. Recombinant bacteriophage lysins as antibacterials.

    PubMed

    Fenton, Mark; Ross, Paul; McAuliffe, Olivia; O'Mahony, Jim; Coffey, Aidan

    2010-01-01

    With the increasing worldwide prevalence of antibiotic resistant bacteria, bacteriophage endolysins (lysins) represent a very promising novel alternative class of antibacterial in the fight against infectious disease. Lysins are phage-encoded peptidoglycan hydrolases which, when applied exogenously (as purified recombinant proteins) to Gram-positive bacteria, bring about rapid lysis and death of the bacterial cell. A number of studies have recently demonstrated the strong potential of these enzymes in human and veterinary medicine to control and treat pathogens on mucosal surfaces and in systemic infections. They also have potential in diagnostics and detection, bio-defence, elimination of food pathogens and control of phytopathogens. This review discusses the extensive research on recombinant bacteriophage lysins in the context of antibacterials, and looks forward to future development and potential. PMID:21327123

  5. Bacillus anthracis and antibacterial agents.

    PubMed

    Bryskier, A

    2002-08-01

    Anthrax is one of the oldest threats to humankind, and remains endemic in animals in many parts of the world. Human cases are infrequent, and some result from biological warfare. This review summarizes the current knowledge on the antibacterial activity of available antibiotics. For potential use in the most severe cases of anthrax, antibacterials need to exhibit potent in vitro activity, intracellular bioactivity, and suitable locations in lymph nodes. In animal models, it has been shown that doxycycline and fluoroquinolones are the most active compounds. There is a lack of data for animal models for macrolides and ketolides, some of them exhibiting good in vitro activity. However, systemic anthrax (inhalation or gastrointestinal) is mainly due to anthrax toxin, and therapy directed against intoxication is needed as basic treatment. PMID:12197869

  6. Washable and antibacterial superhydrophbic fabric

    NASA Astrophysics Data System (ADS)

    Ou, Junfei; Wang, Zhile; Wang, Fajun; Xue, Mingshan; Li, Wen; Amirfazli, Alidad

    2016-02-01

    Inspired by the high adherence of mussel and the excellent water repellency of lotus leaf, superhydrophobic fabric is fabricated via the sequential deposition of polydopamine, Ag2O, and 1H,1H,2H,2H-perfluorodecanethiol, which shows excellent washability and high anti-bacterial activity due to the strong interfacial interaction and the surface silver species as well as the non-wettability, respectively.

  7. Indirect conductimetric assay of antibacterial activities.

    PubMed

    Sawai, J; Doi, R; Maekawa, Y; Yoshikawa, T; Kojima, H

    2002-11-01

    The applicability of indirect conductimetric assays for evaluation of antibacterial activity was examined. The minimal inhibitory concentration (MIC) obtained by the indirect method was consistent with that by the direct conductimetric assay and the turbidity method. The indirect assay allows use of growth media, which cannot be used in the direct conductimetric assay, making it possible to evaluate the antibacterial activity of insoluble or slightly soluble materials with high turbidity, such as antibacterial ceramic powders. PMID:12407467

  8. Antibacterial and Antifungal Compounds from Marine Fungi

    PubMed Central

    Xu, Lijian; Meng, Wei; Cao, Cong; Wang, Jian; Shan, Wenjun; Wang, Qinggui

    2015-01-01

    This paper reviews 116 new compounds with antifungal or antibacterial activities as well as 169 other known antimicrobial compounds, with a specific focus on January 2010 through March 2015. Furthermore, the phylogeny of the fungi producing these antibacterial or antifungal compounds was analyzed. The new methods used to isolate marine fungi that possess antibacterial or antifungal activities as well as the relationship between structure and activity are shown in this review. PMID:26042616

  9. Susceptibility patterns of enteroaggregative Escherichia coli associated with traveller's diarrhoea: emergence of quinolone resistance.

    PubMed

    Vila, J; Vargas, M; Ruiz, J; Espasa, M; Pujol, M; Corachán, M; Jiménez de Anta, M T; Gascón, J

    2001-11-01

    Enteroaggregative Escherichia coli (EAggEC) isolates were identified as a cause of traveller's diarrhoea in 50 (9%) of 517 patients and their antimicrobial susceptibility was determined. Molecular epidemiological characterisation and investigation of the mechanisms of acquisition of quinolone resistance among nalidixic acid-resistant EAggEC strains was performed. Seventeen (34%) of 50 patients needed antimicrobial therapy, because of persistence of symptoms in nine cases and the severity of symptoms in eight cases. Ampicillin and tetracycline resistance was high, whereas chloramphenicol and co-trimoxazole showed moderate activity and amoxicillin plus clavulanic acid, nalidixic acid and ciprofloxacin showed very good activity. Resistance to nalidixic acid was demonstrated in three isolates, two from patients who had travelled to India. In all three strains the resistance was linked to mutations in the gyrA gene alone or in both gyrA and parC genes. Although ciprofloxacin shows excellent in-vitro activity and could be useful in the treatment of traveller's diarrhoea in patients travelling abroad, it may not be useful in patients who have journeyed to India or to Mexico. PMID:11699598

  10. Clonal Expansion May Account for High Levels of Quinolone Resistance in Salmonella enterica Serovar Enteritidis

    PubMed Central

    Kilmartin, Donna; Morris, D.; O'Hare, C.; Corbett-Feeney, G.; Cormican, M.

    2005-01-01

    We have observed a high incidence of isolated nalidixic acid resistance in Salmonella enterica serovar Enteritidis isolates in Ireland, particularly isolates of phage type 1 (PT1). A group of nalidixic acid-resistant (n = 22) and nalidixic acid-susceptible (n = 28) isolates of serovar Enteritidis from multiple sites in Ireland were selected. Isolates were typed by pulsed-field gel electrophoresis (PFGE) with XbaI, and the MICs for nalidixic acid and ciprofloxacin were determined. Mutations associated with nalidixic acid resistance in clinical isolates and laboratory mutants of serovar Enteritidis and 32 nalidixic acid-resistant isolates of 15 other salmonella serovars were identified. PFGE had limited discriminatory power. A specific point mutation (G246T) associated with amino acid substitution Asp87Tyr in the quinolone resistance determining region of the gyrA gene accounted for 95% of all mutations in serovar Enteritidis and for all mutations in PT1 isolates. Greater diversity of mutations was observed among all non-Enteritidis salmonella serovars studied. Rates of nalidixic acid resistance in serovar Enteritidis may predominantly reflect clonal expansion after infrequent mutation or selection events. PMID:15870349

  11. Therapeutic effects of an injectable new quinolone, pazufloxacin, against polymicrobial infections in the uterine endometritis model.

    PubMed

    Mikamo, H; Kawazoe, K; Sato, Y; Tamaya, T

    1998-01-01

    Polymicrobial infections with aerobes and anaerobes are common in female genital tract infections. We evaluated the efficacy of an injectable new quinolon, pazufloxacin, using a uterine endometritis model. Rats were infected with a mixed inoculation of Escherichia coli plus Bacteriodes fragilis (MIC of pazufloxacin and ceftazidime: E. coli: 0.05 and 1.56 micrograms/ml, respectively, B. fragilis: 3.13 and 3.13 micrograms/ml, respectively). After inoculating 10(7) cfu/rat of each organism, pazufloxacin or ceftazidime (10 or 20 mg/kg, respectively, i.v., b.i.d., 3 days) was administered and compared with the nontreated group. The viable cell counts of the uterine corpus and uterine cervix in pazufloxacin-treated and ceftazidime-treated groups were decreased, compared with the nontreated group. The viable cell counts of the adnexa in the pazufloxacin-treated group were significantly decreased, compared with the ceftazidimetreated group. These results suggest that pazufloxacin would be useful for the treatment of polymicrobial infections, especially adnexitis. PMID:9551239

  12. Tandem Prenyltransferases Catalyze Isoprenoid Elongation and Complexity Generation in Biosynthesis of Quinolone Alkaloids

    PubMed Central

    Zou, Yi; Zhan, Zhajun; Li, Dehai; Tang, Mancheng; Watanabe, Kenji; Tang, Yi

    2015-01-01

    Modification of natural products with prenyl groups and the ensuing oxidative transformations are important for introducing structural complexity and biological activities. Understanding the different mechanisms Nature performs prenylation can lead to new enzymatic tools. Penigequinolones (1) are potent insecticidal alkaloids that contain a highly modified ten-carbon prenyl group. Here we reveal an iterative prenylation mechanism for installing the ten-carbon unit using two aromatic prenyltransferases (PenI and PenG) present in the gene cluster of 1 from Penicillium thymicola. The initial Friedel-Crafts alkylation is catalyzed by PenI to yield the dimethylallyl quinolone 6. The five-carbon side chain is then dehydrogenated by a Flavin-dependent monooxygenase to an aryldiene 9, which serves as the electron-rich substrate for a second alkylation with dimethylallyl diphosphate to yield a stryrenyl product 10. The completed, oxidized ten-carbon prenyl group is then shown to undergo further structural morphing to yield yaequinolone C 12, the immediate precursor of 1. Our studies therefore uncover an unprecedented prenyl chain extension mechanism in natural product biosynthesis. PMID:25859931

  13. Application of Sigmoidal Transformation Functions in Optimization of Micellar Liquid Chromatographic Separation of Six Quinolone Antibiotics.

    PubMed

    Hadjmohammadi, Mohammadreza; Salary, Mina

    2016-03-01

    A chemometrics approach has been used to optimize the separation of six quinolone compounds by micellar liquid chromatography (MLC). A Derringer's desirability function, a multicriteria decision-making (MCDM) method, was tested for evaluation of two different measures of chromatographic performance (resolution and analysis time). The effect of three experimental parameters on a chromatographic response function (CRF) expressed as a product of two sigmoidal desirability functions was investigated. The sigmoidal functions were used to transform the optimization criteria, resolution and analysis time into the desirability values. The factors studied were the concentration of sodium dodecyl sulfate, butanol content and pH of the mobile phase. The experiments were done according to the face-centered cube central composite design, and the calculated CRF values were fitted to a polynomial model to correlate the CRF values with the variables and their interactions. The developed regression model showed good descriptive and predictive ability (R(2) = 0.815, F = 6.919, SE = 0.038, [Formula: see text]) and used, by a grid search algorithm, to optimize the chromatographic conditions for the separation of the mixture. The efficiency of prediction of polynomial model was confirmed by performing the experiment under the optimal conditions. PMID:26590234

  14. Conformational analysis of a quinolonic ribonucleoside with anti-HSV-1 activity

    NASA Astrophysics Data System (ADS)

    Yoneda, Julliane D.; Velloso, Marcia Helena R.; Leal, Kátia Z.; Azeredo, Rodrigo B. de V.; Sugiura, Makiko; Albuquerque, Magaly G.; Santos, Fernanda da C.; Souza, Maria Cecília B. V. de; Cunha, Anna Claudia; Seidl, Peter R.; Alencastro, Ricardo B. de; Ferreira, Vitor F.

    2011-01-01

    The infections caused by the Herpes Simplex Virus are one of the most common sources of diseases in adults and several natural nucleoside analogues are currently used in the treatment of these infections. In vitro tests of a series of quinolonic ribonucleosides derivatives synthesized by part of our group indicated that some of them have antiviral activity against HSV-1. The conformational analysis of bioactive compounds is extremely important in order to better understand their chemical structures and biological activity. In this work, we have carried out a nuclear relaxation NMR study of 6-Me ribonucleoside derivative in order to determine if the syn or anti conformation is preferential. The NMR analysis permits the determination of inter-atomic distances by using techniques which are based on nuclear relaxation and related phenomena. Those techniques are non-selective longitudinal or spin-lattice relaxation rates and NULL pulse sequence, which allow the determination of distances between pairs of hydrogen atoms. The results of NMR studies were compared with those obtained by molecular modeling.

  15. In Vitro Activity of Nemonoxacin, a Novel Nonfluorinated Quinolone, against 2,440 Clinical Isolates?

    PubMed Central

    Adam, Heather J.; Laing, Nancy M.; King, C. Richard; Lulashnyk, Ben; Hoban, Daryl J.; Zhanel, George G.

    2009-01-01

    The in vitro activity of nemonoxacin (TG-873870), a novel nonfluorinated quinolone, was tested against 2,440 clinical isolates. Nemonoxacin was at least fourfold more active than levofloxacin and moxifloxacin against most gram-positive cocci tested (shown by the following MIC90/range [?g/ml] values; community-associated methicillin [meticillin]-resistant Staphylococcus aureus, 0.5/0.015 to 2; Staphylococcus epidermidis, 0.5/0.015 to 4 for methicillin-susceptible staphylococci and 2/0.12 to 2 for methicillin-resistant staphylococci; Streptococcus pneumoniae, 0.015/?0.008 to 0.25; Enterococcus faecalis, 1/0.03 to 128). Nemonoxacin activity against gram-negative bacilli was similar to levofloxacin and moxifloxacin (MIC90/range [?g/ml]; Escherichia coli, 32/?0.015 to ?512; Klebsiella pneumoniae, 2/?0.015 to 128; K. oxytoca, 0.5/0.06 to 1; Proteus mirabilis, 16/0.25 to ?512; Pseudomonas aeruginosa, 32/?0.015 to ?512; Acinetobacter baumannii, 1/0.12 to 16). PMID:19738018

  16. In vitro activity of nemonoxacin, a novel nonfluorinated quinolone, against 2,440 clinical isolates.

    PubMed

    Adam, Heather J; Laing, Nancy M; King, C Richard; Lulashnyk, Ben; Hoban, Daryl J; Zhanel, George G

    2009-11-01

    The in vitro activity of nemonoxacin (TG-873870), a novel nonfluorinated quinolone, was tested against 2,440 clinical isolates. Nemonoxacin was at least fourfold more active than levofloxacin and moxifloxacin against most gram-positive cocci tested (shown by the following MIC(90)/range [microg/ml] values; community-associated methicillin [meticillin]-resistant Staphylococcus aureus, 0.5/0.015 to 2; Staphylococcus epidermidis, 0.5/0.015 to 4 for methicillin-susceptible staphylococci and 2/0.12 to 2 for methicillin-resistant staphylococci; Streptococcus pneumoniae, 0.015/< or = 0.008 to 0.25; Enterococcus faecalis, 1/0.03 to 128). Nemonoxacin activity against gram-negative bacilli was similar to levofloxacin and moxifloxacin (MIC(90)/range [microg/ml]; Escherichia coli, 32/< or = 0.015 to > or = 512; Klebsiella pneumoniae, 2/< or = 0.015 to 128; K. oxytoca, 0.5/0.06 to 1; Proteus mirabilis, 16/0.25 to > or = 512; Pseudomonas aeruginosa, 32/< or = 0.015 to > or = 512; Acinetobacter baumannii, 1/0.12 to 16). PMID:19738018

  17. Synthesis, antifungal and antibacterial activity of novel 1,2,4-triazole derivatives

    PubMed Central

    Gupta, Deepa; Jain, D. K.

    2015-01-01

    A large number of 1,2,4-triazole-containing ring system have been incorporated into a wide variety of therapeutically interesting drug candidates including anti-inflammatory, central nervous system stimulants, antianxiety, and antimicrobial agents. To overcome the rapid development of drug resistance, new agents should preferably have chemical characteristics that clearly differ from those of existing agents. Thus led to the design and synthesize the new antimicrobial agents. A novel series of Schiff bases based on of 4-(benzylideneamino)-5-phenyl-4H-1,2,4-triazole-3-thiol scaffold was prepared by heating thiocarbohydrazide and substituted benzoic acid and subsequently, treating with substituted benzaldehydes. Seventeen derivatives were synthesized and were biologically screened for antifungal and antibacterial activity. The newly synthesized derivatives of triazole showed antifungal activity against fungal species, Microsporum gypseum; and antibacterial activity against bacterial species, Staphylococcus aureus. It was observed that none of the compounds tested showed positive results for fungi Candida albicans fungi Aspergillus niger, nor against bacterial strain Escherichia coli. Strong antifungal effects were obtained for the synthesized compounds against M. gypseum and were superior or comparable to standard drug ketoconazole. Similarly, all of the synthesized compounds exhibit strong antibacterial activity against S. aureus and were superior or comparable to standard drug streptomycin. It was found that among the triazole derivatives so synthesized, six of them, showed antifungal activity superior to ketoconazole while one of them, showed antibacterial activity superior to streptomycin. Thus, these can be the potential new molecule as an antimicrobial agent. PMID:26317080

  18. Lysozyme-Based Antibacterial Nanomotors.

    PubMed

    Kiristi, Melek; Singh, Virendra V; Esteban-Fernández de Ávila, Berta; Uygun, Murat; Soto, Fernando; Aktaş Uygun, Deniz; Wang, Joseph

    2015-09-22

    An effective and rapid bacterial killing nanotechnology strategy based on lysozyme-modified fuel-free nanomotors is demonstrated. The efficient antibacterial property of lysozyme, associated with the cleavage of glycosidic bonds of peptidoglycans present in the bacteria cell wall, has been combined with ultrasound (US)-propelled porous gold nanowire (p-AuNW) motors as biocompatible dynamic bacteria nanofighters. Coupling the antibacterial activity of the enzyme with the rapid movement of these p-AuNWs, along with the corresponding fluid dynamics, promotes enzyme-bacteria interactions and prevents surface aggregation of dead bacteria, resulting in a greatly enhanced bacteria-killing capability. The large active surface area of these nanoporous motors offers a significantly higher enzyme loading capacity compared to nonporous AuNWs, which results in a higher antimicrobial activity against Gram-positive and Gram-negative bacteria. Detailed characterization studies and control experiments provide useful insights into the underlying factors controlling the antibacterial performance of the new dynamic bacteria nanofighters. Rapid and effective killing of the Gram-positive Micrococcus lysodeikticus bacteria (69-84% within 1-5 min) is demonstrated. PMID:26308491

  19. Antibacterial Derivatives of Ciprofloxacin to Inhibit Growth of Necrotizing Fasciitis Associated Penicillin Resistant Escherichia coli

    PubMed Central

    Bartzatt, Ronald; Cirillo, Suat L. G.; Cirillo, Jeffrey D.

    2013-01-01

    Escherichia coli (E. coli) is associated with necrotizing fasciitis (type I) and can induce enough damage to tissue causing hypoxia. Three ester derivatives of the broad-spectrum antibiotic ciprofloxacin were placed into bacteria culture simultaneously with the parent ciprofloxacin (drug 1) to ascertain the level of antibacterial activity. The n-propyl (drug 2), n-pentyl (drug 3), and n-octyl (drug 4) esters of ciprofloxacin were synthesized under mixed phase conditions and by microwave excitation. The formation of ester derivatives of ciprofloxacin modified important molecular properties such as Log P and polar surface area which improves tissue penetration, yet preserved strong antibacterial activity. The Log P values for drugs 1, 2, 3, and 4 became ?0.701, 0.437, 1.50, and 3.02, respectively. The polar surface areas for drugs 1, 2, 3, and 4 were determined to be 74.6 Angstroms2, 63.6 Angstroms2, 63.6 Angstroms2, and 63.6 Angstroms2, respectively. These values of Log P and polar surface area improved tissue penetration, as indicated by the determination of dermal permeability coefficient (Kp) and subsequently into the superficial fascial layer. All drugs induced greater than 60% bacterial cell death at concentrations less than 1.0 micrograms/milliliter. The ester derivatives of ciprofloxacin showed strong antibacterial activity toward penicillin resistant E. coli. PMID:26555983

  20. Antibacterial Mechanism of (-)-Nortrachelogenin in Escherichia coli O157.

    PubMed

    Lee, Heejeong; Ji, Young Rae; Ryoo, Zae Young; Choi, Myung-Sook; Woo, Eun-Rhan; Lee, Dong Gun

    2016-01-01

    (-)-Nortrachelogenin is a lignan belonging to group of polyphenolic compounds. Its biological properties in mammalian cells are well-studied; however, its biological effects in microorganisms remain poorly understood. Its efficacy against pathogenic bacteria, including antibiotic-resistant strains, was investigated and it was found that bacteria are highly susceptible to the antibacterial effects of this compound. To investigate the antibacterial mode of action(s) against Escherichia coli O157, its effect on the penetration of SYTOX green into bacterial cells was assayed. The penetration of SYTOX Green into a bacterial cell is a measure of permeability of the plasma membrane. An increase in fluorescence intensity using bis-(1,3-dibutylbarbituric acid) trimethine oxonol [DiBAC4(3)] and 3,3'-dipropylthiacarbocyanine iodide [DiSC3(5)] was also observed, indicating membrane depolarization. Potassium ion efflux from the cytosol into the extracellular matrix showed that cellular damage due to (-)-nortrachelogenin treatment resulted in the loss of intracellular components. While cells were damaged by (-)-nortrachelogenin, large unilamellar vesicles containing fluorescein isothiocyanate-dextran were perturbed to migrate molecules between 3.3 and 4.8 nm. The release of calcein from giant unilamellar vesicles, occurring as a result of disruption in artificial membranes, was visualized. Taken together, our results indicate that (-)-nortrachelogenin exerts its antibacterial effect by disorganizing and perturbing the cytoplasmic membrane, demonstrating the potential of this compound as a candidate for antibiotic drug development. PMID:26420306

  1. Synthesis of novel bisindolylmethane Schiff bases and their antibacterial activity.

    PubMed

    Imran, Syahrul; Taha, Muhammad; Ismail, Nor Hadiani; Khan, Khalid Mohammed; Naz, Farzana; Hussain, Memona; Tauseef, Saima

    2014-01-01

    In an effort to develop new antibacterial drugs, some novel bisindolylmethane derivatives containing Schiff base moieties were prepared and screened for their antibacterial activity. The synthesis of the bisindolylmethane Schiff base derivatives 3-26 was carried out in three steps. First, the nitro group of 3,3'-((4-nitrophenyl)-methylene)bis(1H-indole) (1) was reduced to give the amino substituted bisindolylmethane 2 without affecting the unsaturation of the bisindolylmethane moiety using nickel boride in situ generated. Reduction of compound 1 using various catalysts showed that combination of sodium borohydride and nickel acetate provides the highest yield for compound 2. Bisindolylmethane Schiff base derivatives were synthesized by coupling various benzaldehydes with amino substituted bisindolylmethane 2. All synthesized compounds were characterized by various spectroscopic methods. The bisindolylmethane Schiff base derivatives were evaluated against selected Gram-positive and Gram-negative bacterial strains. Derivatives having halogen and nitro substituent display weak to moderate antibacterial activity against Salmonella typhi, S. paratyphi A and S. paratyphi B. PMID:25102118

  2. Antibacterial Surgical Silk Sutures Using a High-Performance Slow-Release Carrier Coating System.

    PubMed

    Chen, Xiaojie; Hou, Dandan; Wang, Lu; Zhang, Qian; Zou, Jiahan; Sun, Gang

    2015-10-14

    Sutures are a vital part for surgical operation, and suture-associated surgical site infections are an important issue of postoperative care. Antibacterial sutures have been proved to reduce challenging complications caused by bacterial infections. In recent decades, triclosan-free sutures have been on their way to commercialization. Alternative antibacterial substances are becoming relevant to processing surgical suture materials. Most of the antibacterial substances are loaded directly on sutures by dipping or coating methods. The aim of this study was to optimize novel antibacterial braided silk sutures based on levofloxacin hydrochloride and poly(ε-caprolactone) by two different processing sequences, to achieve suture materials with slow-release antibacterial efficacy and ideal physical and handling properties. Silk strands were processed into sutures on a circular braiding machine, and antibacterial treatment was introduced alternatively before or after braiding by two-dipping-two-rolling method (M1 group and M2 group). The antibacterial activity and durability against Staphylococcus aureus and Escherichia coli were tested. Drug release profiles were measured in phosphate buffer with different pH values, and release kinetics model was built to analyze the sustained drug release mechanism between the interface of biomaterials and the in vitro aqueous environment. Knot-pull tensile strength, thread-to-thread friction, and bending stiffness were determined to evaluate physical and handling properties of sutures. All coated sutures showed continuous antibacterial efficacy and slow drug release features for more than 5 days. Besides, treated sutures fulfilled U.S. Pharmacopoeia required knot-pull tensile strength. The thread-to-thread friction and bending stiffness for the M1 group changed slightly when compared with those of uncoated ones. However, physical and handling characteristics of the M2 group tend to approach those of monofilament ones. The novel suture showed acceptable in vitro cytotoxicity according to ISO 10993-5. Generally speaking, all coated sutures show potential in acting as antibacterial suture materials, and M1 group is proved to have a higher prospect for clinical applications. PMID:26378964

  3. Relationship between mutations in the gyrA gene and quinolone resistance in clinical isolates of Corynebacterium striatum and Corynebacterium amycolatum.

    PubMed

    Sierra, Josep M; Martinez-Martinez, Luis; Vázquez, Fernando; Giralt, Ernest; Vila, Jordi

    2005-05-01

    Quinolone susceptibility was analyzed in 17 clinical isolates of Corynebacterium striatum and 9 strains of Corynebacterium amycolatum by the E-test method in Mueller-Hinton agar plates. The C. striatum ATCC 6940 strain was used as a control strain. The amplified quinolone resistance determining regions of the gyrA genes of C. amycolatum and C. striatum were characterized. Four in vitro quinolone-resistant mutants of C. amycolatum were selected and analyzed. Both in vivo and in vitro quinolone-resistant strains of C. amycolatum showed high levels of fluoroquinolone resistance in strains with a double mutation leading to an amino acid change in positions 87 and 91 or positions 87 and 88 (unusual mutation) of GyrA, whereas the same concomitant mutations at amino acid positions 87 and 91 in GyrA of C. striatum produced high levels of resistance to ciprofloxacin and levofloxacin but only showed a moderate increase in the MIC of moxifloxacin, suggesting that other mechanism(s) of quinolone resistance could be involved in moxifloxacin resistance in C. amycolatum. Moreover, a PCR-RFLP-NcoI of the gyrA gene was developed to distinguish between C. amycolatum and C. striatum species. PMID:15855486

  4. Fatty acid biosynthesis as a target for novel antibacterials

    PubMed Central

    Rock, Charles O

    2006-01-01

    The bacterial fatty acid synthesis pathway has significant potential as a target for the development of novel antibacterials. The pathway has been extensively studied in Escherichia coli, the crystal structures of the compounds involved are known and homologous genes are readily identified in the genomes of important pathogens. The, currently used drugs triclosan and isoniazid are known to target one step in the pathway. Other experimental compounds such as thiolactomycin and cerulenin effectively inhibit other steps. These known pathway inhibitors are reviewed and the areas for potential future developments are explored. PMID:15043388

  5. Antibacterial mechanisms identified through structural systems pharmacology

    PubMed Central

    2013-01-01

    Background The growing discipline of structural systems pharmacology is applied prospectively in this study to predict pharmacological outcomes of antibacterial compounds in Escherichia coli K12. This work builds upon previously established methods for structural prediction of ligand binding pockets on protein molecules and utilizes and expands upon the previously developed genome scale model of metabolism integrated with protein structures (GEM-PRO) for E. coli, structurally accounting for protein complexes. Carefully selected case studies are demonstrated to display the potential for this structural systems pharmacology framework in discovery and development of antibacterial compounds. Results The prediction framework for antibacterial activity of compounds was validated for a control set of well-studied compounds, recapitulating experimentally-determined protein binding interactions and deleterious growth phenotypes resulting from these interactions. The antibacterial activity of fosfomycin, sulfathiazole, and trimethoprim were accurately predicted, and as a negative control glucose was found to have no predicted antibacterial activity. Previously uncharacterized mechanisms of action were predicted for compounds with known antibacterial properties, including (1-hydroxyheptane-1,1-diyl)bis(phosphonic acid) and cholesteryl oleate. Five candidate inhibitors were predicted for a desirable target protein without any known inhibitors, tryptophan synthase β subunit (TrpB). In addition to the predictions presented, this effort also included significant expansion of the previously developed GEM-PRO to account for physiological assemblies of protein complex structures with activities included in the E. coli K12 metabolic network. Conclusions The structural systems pharmacology framework presented in this study was shown to be effective in the prediction of molecular mechanisms of antibacterial compounds. The study provides a promising proof of principle for such an approach to antibacterial development and raises specific molecular and systemic hypotheses about antibacterials that are amenable to experimental testing. This framework, and perhaps also the specific predictions of antibacterials, is extensible to developing antibacterial treatments for pathogenic E. coli and other bacterial pathogens. PMID:24112686

  6. [Two chapters from the medical history of this century: antibacterial therapy].

    PubMed

    Bol, P

    1999-02-13

    The antibiotic era brought adequate therapies for bacterial infections and began with the introduction of sulphonamides (discovered earlier by Domagk) in 1935 and penicillins (discovered earlier by Fleming) in the course of World War II. Notwithstanding the usual description as 'discoveries', they were the fruits of systematic investigations for chemicals with antibacterial properties and little or no toxicity for the host. Despite the role of serendipity in the discovery of penicillin, the bactericidal moulds that Fleming observed had fallen on fertile soil: a laboratory where the search for antibacterial drugs had been going on for years. PMID:10221100

  7. Thiourea derivatives incorporating a hippuric acid moiety: synthesis and evaluation of antibacterial and antifungal activities.

    PubMed

    Abbas, Samir Y; El-Sharief, Marwa A M Sh; Basyouni, Wahid M; Fakhr, Issa M I; El-Gammal, Eman W

    2013-06-01

    New series of thiourea derivatives incorporating a hippuric acid moiety have been synthesized through the reaction of 4-hippuric acid isothiocyanate with various nitrogen nucleophiles such as aliphatic amines, aromatic amines, sulfa drugs, aminopyrazoles, phenylhydrazine and hydrazides. The synthesized compounds were tested against bacterial and fungal strains. Most of compounds, such as 2-(4-(3-(3-bromophenyl)thioureido)benzamido)acetic acid and 2-(4-(3-(4-(N-pyrimidin-2-ylsulfamoyl)phenyl)thioureido)benzamido)acetic acid, showed significant antibacterial and antifungal activities. These compounds comprise a new class of promising broad-spectrum antibacterial and antifungal agents. PMID:23644194

  8. Fabrication of silver-coated cobalt ferrite nanocomposite and the study of its antibacterial activity

    NASA Astrophysics Data System (ADS)

    Kooti, M.; Saiahi, S.; Motamedi, H.

    2013-05-01

    A new silver coated cobalt ferrite nanocomposite, Ag@CoFe2O4, was prepared by a two-step procedure. In the first step, cobalt ferrite nanoparticles were synthesized by a combustion method using glycine as a fuel. This ferrite was then coated with nanosilver via chemical reduction of Ag+ solution. The as-synthesized Ag@CoFe2O4 was characterized by X-ray diffraction, transmission electron microscopy, and vibrating sample magnetometer. The antibacterial activity of this composite was investigated against some Gram-positive and Gram-negative bacteria and compared with those of silver nanoparticles and some standard antibacterial drugs.

  9. Impacts of coexisting antibiotics, antibacterial residues, and heavy metals on the occurrence of erythromycin resistance genes in urban wastewater.

    PubMed

    Gao, Pin; He, Shi; Huang, Shenglin; Li, Kanzhu; Liu, Zhenhong; Xue, Gang; Sun, Weimin

    2015-05-01

    Antibiotic resistance is a global challenge and represents a growing threat on human health worldwide. Wastewater treatment plants (WWTPs) are generally considered as hotspots for control and/or dissemination of antibiotic resistance. The role of antibiotics, antibacterial residues, and heavy metals played on the evolution and spread of antibiotic resistance is still not well understood. Here, the occurrence of antibiotics (i.e., macrolides, tetracyclines, sulfonamides, and quinolones), antibacterial residues (i.e., triclosan), as well as heavy metals (i.e., cadmium, chromium, copper, zinc, lead, and nickel) in urban wastewater was investigated. Also, the abundances of erythromycin resistance genes (ERY-ARGs) including ere(A), ere(B), mef(A)/mef(E), erm(A), erm(B), erm(C), and msr(A)/msr(B) genes were screened. A relationship between certain antibiotics, antibacterial residues, and heavy metals and ERY-ARGs was demonstrated. ERY presented significant correlations (0.883 < r < 0.929, P < 0.05) with ere(A), ere(B), and mef(A)/mef(E) genes, while tetracycline exhibited a significant correlation (r = 0.829, P < 0.05) with erm(B) genes. It is noteworthy that triclosan correlated significantly (0.859 < r < 0.956, P < 0.05) with ere(A), ere(B), mef(A)/mef(E), and erm(B) genes. In addition, significantly positive correlations (0.823 < r < 0.871, P < 0.05) were observed between zinc and lead and certain ERY-ARGs (i.e., ere(B), mef(A)/mef(E), erm(B), etc.). Further investigations should be involved to elucidate the co-selection and/or cross-selection mechanisms due to co-existence of these selective factors in urban wastewater. PMID:25631280

  10. Stereoselective permeation of new fluorinated quinolone derivatives across LLC-PK1 cell monolayers.

    PubMed

    Sasaya, M; Hatakeyama, Y; Saitoh, H; Takada, M

    1999-07-01

    We examined the stereoselective membrane permeation of new fluorinated quinolone derivatives (NQs) across LLC-PK1 cell monolayers, using levofloxacin (LVFX) and its R-(+) isomer. LVFX permeation was 1.6-fold greater in the basal-to-apical direction than that in the apical-to-basal direction, suggesting that LVFX permeated LLC-PK1 cell monolayers in a secretory-oriented manner. In contrast to LVFX, the permeation of the R-(+) isomer was almost identical in both directions. LVFX permeation in the basal-to-apical direction was significantly reduced in the presence of guanidine, enoxacin, and L-arginine, whereas tetraethylammonium, D-arginine, D- and L-lysine had no effect on the basal-to-apical permeation of LVFX. Basal-to-apical permeation of the R-(+) isomer was not affected by these compounds. Cellular accumulation of LVFX was inversely increased when guanidine suppressed the appearance of LVFX in the apical medium in a concentration-dependent manner. These results imply that the inhibitory effect of guanidine on the basal-to-apical permeation of LVFX involves the permeation process across the apical membrane. Guanidine trans-stimulated the efflux of LVFX from LLC-PK1 cells but did not affect cimetidine efflux. These results suggest that some NQs, like LVFX and its R-(+) isomer, are stereoselectively secreted across LLC-PK1 cell monolayers and that an organic cation transport system, which favors guanidine as a typical substrate, may be involved in the secretory-oriented permeation of some NQs. PMID:10443467

  11. Susceptibility to β-lactams and quinolones of Enterobacteriaceae isolated from urinary tract infections in outpatients.

    PubMed

    Marchisio, Martín; Porto, Ayelén; Joris, Romina; Rico, Marina; Baroni, María R; Di Conza, José

    2015-12-01

    The antibiotic susceptibility profile was evaluated in 71 Enterobacteriaceae isolates obtained from outpatient urine cultures in July 2010 from two health institutions in Santa Fe, Argentina. The highest rates of antibiotic resistance were observed for ampicillin (AMP) (69%), trimethoprim/sulfamethoxazole (TMS) (33%), and ciprofloxacin (CIP) (25%). Meanwhile, 21% of the isolates were resistant to three or more tested antibiotics families. Thirty integron-containing bacteria (42.3%) were detected, and a strong association with TMS resistance was found. Third generation cephalosporin resistance was detected in only one Escherichia coli isolate, and it was characterized as a blaCMY-2 carrier. No plasmid-mediated quinolone resistance (PMQR) was found. Resistance to fluoroquinolone in the isolates was due to alterations in QRDR regions. Two mutations in GyrA (S83L, D87N) and one in ParC (S80I) were observed in all CIP-resistant E. coli. It was determined to be the main phylogenetic groups in E. coli isolates. Minimum Inhibitory Concentration (MIC) values against nalidixic acid (NAL), levofloxacin (LEV), and CIP were determined for 63 uropathogenic E. coli isolates as MIC50 of 4 μg/mL, 0.03125 μg/mL, and 0.03125 μg/mL, respectively, while the MIC90 values of the antibiotics were determined as 1024 μg/mL, 64 μg/mL, and 16 μg/mL, respectively. An association between the phylogenetic groups, A and B1 with fluoroquinolone resistance was observed. These results point to the importance of awareness of the potential risk associated with empirical treatment with both the families of antibiotics. PMID:26691475

  12. Susceptibility to β-lactams and quinolones of Enterobacteriaceae isolated from urinary tract infections in outpatients

    PubMed Central

    Marchisio, Martín; Porto, Ayelén; Joris, Romina; Rico, Marina; Baroni, María R.; Di Conza, José

    2015-01-01

    Abstract The antibiotic susceptibility profile was evaluated in 71 Enterobacteriaceae isolates obtained from outpatient urine cultures in July 2010 from two health institutions in Santa Fe, Argentina. The highest rates of antibiotic resistance were observed for ampicillin (AMP) (69%), trimethoprim/sulfamethoxazole (TMS) (33%), and ciprofloxacin (CIP) (25%). Meanwhile, 21% of the isolates were resistant to three or more tested antibiotics families. Thirty integron-containing bacteria (42.3%) were detected, and a strong association with TMS resistance was found. Third generation cephalosporin resistance was detected in only one Escherichia coli isolate, and it was characterized as a bla CMY-2 carrier. No plasmid-mediated quinolone resistance (PMQR) was found. Resistance to fluoroquinolone in the isolates was due to alterations in QRDR regions. Two mutations in GyrA (S83L, D87N) and one in ParC (S80I) were observed in all CIP-resistant E. coli. It was determined to be the main phylogenetic groups in E. coli isolates. Minimum Inhibitory Concentration (MIC) values against nalidixic acid (NAL), levofloxacin (LEV), and CIP were determined for 63 uropathogenic E. coli isolates as MIC50 of 4 μg/mL, 0.03125 μg/mL, and 0.03125 μg/mL, respectively, while the MIC90 values of the antibiotics were determined as 1024 μg/mL, 64 μg/mL, and 16 μg/mL, respectively. An association between the phylogenetic groups, A and B1 with fluoroquinolone resistance was observed. These results point to the importance of awareness of the potential risk associated with empirical treatment with both the families of antibiotics. PMID:26691475

  13. Plasmid-mediated quinolone resistance genes in fecal bacteria from rooks commonly wintering throughout Europe.

    PubMed

    Literak, Ivan; Micudova, Maria; Tausova, Dagmar; Cizek, Alois; Dolejska, Monika; Papousek, Ivo; Prochazka, Jakub; Vojtech, Jiri; Borleis, Frank; Guardone, Lisa; Guenther, Sebastian; Hordowski, Jozef; Lejas, Cyrille; Meissner, Wlodzimierz; Marcos, Benito Fuertes; Tucakov, Marko

    2012-12-01

    This study concerned the occurrence of fecal bacteria with plasmid-mediated quinolone resistance (PMQR) genes in rooks (Corvus frugilegus, medium-sized corvid birds) wintering in continental Europe during winter 2010/2011. Samples of fresh rook feces were taken by cotton swabs at nine roosting places in eight European countries. Samples were transported to one laboratory and placed in buffered peptone water (BPW). The samples from BPW were enriched and subcultivated onto MacConkey agar (MCA) supplemented with ciprofloxacin (0.06 mg/L) to isolate fluoroquinolone-resistant bacteria. DNA was isolated from smears of bacterial colonies growing on MCA and tested by PCR for PMQR genes aac(6')-Ib, qepA, qnrA, qnrB, qnrC, qnrD, qnrS, and oqxAB. All the PCR products were further analyzed by sequencing. Ciprofloxacin-resistant bacteria were isolated from 37% (392 positive/1,073 examined) of samples. Frequencies of samples with ciprofloxacin-resistant isolates ranged significantly from 3% to 92% in different countries. The qnrS1 gene was found in 154 samples and qnrS2 in 2 samples. The gene aac(6')-Ib-cr was found in 16 samples. Thirteen samples were positive for qnrB genes in variants qnrB6 (one sample), qnrB18 (one), qnrB19 (one), qnrB29 (one), and qnrB49 (new variant) (one). Both the qnrD and oqxAB genes were detected in six samples. The genes qnrA, qnrC, and qepA were not found. Wintering omnivorous rooks in Europe were commonly colonized by bacteria supposedly Enterobacteriaceae with PMQR genes. Rooks may disseminate these epidemiologically important bacteria over long distances and pose a risk for environmental contamination. PMID:22731858

  14. Different Dynamic Patterns of β-Lactams, Quinolones, Glycopeptides and Macrolides on Mouse Gut Microbial Diversity

    PubMed Central

    Wang, Shan; Liao, Shuo-Xi; Peng, Xin; He, Yan; Chen, Yi-Ran; Shen, Hua-Fang; Su, Jin; Chen, Ye; Jiang, Yun-Xia; Zhang, Guo-Xia; Zhou, Hong-Wei

    2015-01-01

    The adverse impact of antibiotics on the gut microbiota has attracted extensive interest, particularly due to the development of microbiome research techniques in recent years. However, a direct comparison of the dynamic effects of various types of antibiotics using the same animal model has not been available. In the present study, we selected six antibiotics from four categories with the broadest clinical usage, namely, β-lactams (Ceftriaxone Sodium, Cefoperazone/Sulbactam and meropenem), quinolones (ofloxacin), glycopeptides (vancomycin), and macrolides (azithromycin), to treat BALB/c mice. Stool samples were collected during and after the administration of antibiotics, and microbial diversity was analyzed through Illumina sequencing and bioinformatics analyses using QIIME. Both α and β diversity analyses showed that ceftriaxone sodium, cefoperazone/sulbactam, meropenem and vancomycin changed the gut microbiota dramatically by the second day of antibiotic administration whereas the influence of ofloxacin was trivial. Azithromycin clearly changed the gut microbiota but much less than vancomycin and the β-lactams. In general, the community changes induced by the three β-lactam antibiotics showed consistency in inhibiting Papillibacter, Prevotella and Alistipes while inducing massive growth of Clostridium. The low diversity and high Clostridium level might be an important cause of Clostridium difficile infection after usage of β-lactams. Vancomycin was unique in that it inhibited Firmicutes, mainly the genus Clostridium. On the other hand, it induced the growth of Escherichia and effect lasted for months afterward. Azithromycin and meropenem induced the growth of Enterococcus. These findings will be useful for understanding the potential adverse effects of antibiotics on the gut microbiome and ensuring their better usage. PMID:25970622

  15. PqsE functions independently of PqsR-Pseudomonas quinolone signal and enhances the rhl quorum-sensing system.

    PubMed

    Farrow, John M; Sund, Zoe M; Ellison, Matthew L; Wade, Dana S; Coleman, James P; Pesci, Everett C

    2008-11-01

    Pseudomonas aeruginosa is an opportunistic pathogen that causes both acute and chronic infections in immunocompromised individuals. This gram-negative bacterium produces a battery of virulence factors that allow it to infect and survive in many different hostile environments. The control of many of these virulence factors falls under the influence of one of three P. aeruginosa cell-to-cell signaling systems. The focus of this study, the quinolone signaling system, functions through the Pseudomonas quinolone signal (PQS), previously identified as 2-heptyl-3-hydroxy-4-quinolone. This signal binds to and activates the LysR-type transcriptional regulator PqsR (also known as MvfR), which in turn induces the expression of the pqsABCDE operon. The first four genes of this operon are required for PQS synthesis, but the fifth gene, pqsE, is not. The function of the pqsE gene is not known, but it is required for the production of multiple PQS-controlled virulence factors and for virulence in multiple models of infection. In this report, we show that PqsE can activate PQS-controlled genes in the absence of PqsR and PQS. Our data also suggest that the regulatory activity of PqsE requires RhlR and indicate that a pqsE mutant can be complemented for pyocyanin production by a large excess of exogenous N-butyryl homoserine lactone (C4-HSL). Finally, we show that PqsE enhances the ability of Escherichia coli expressing RhlR to respond to C4-HSL. Overall, our data lead us to conclude that PqsE functions as a regulator that is independent of PqsR and PQS but dependent on the rhl quorum-sensing system. PMID:18776012

  16. Using second-order calibration method based on trilinear decomposition algorithms coupled with high performance liquid chromatography with diode array detector for determination of quinolones in honey samples.

    PubMed

    Yu, Yong-Jie; Wu, Hai-Long; Shao, Sheng-Zhi; Kang, Chao; Zhao, Juan; Wang, Yu; Zhu, Shao-Hua; Yu, Ru-Qin

    2011-09-15

    A novel strategy that combines the second-order calibration method based on the trilinear decomposition algorithms with high performance liquid chromatography with diode array detector (HPLC-DAD) was developed to mathematically separate the overlapped peaks and to quantify quinolones in honey samples. The HPLC-DAD data were obtained within a short time in isocratic mode. The developed method could be applied to determine 12 quinolones at the same time even in the presence of uncalibrated interfering components in complex background. To access the performance of the proposed strategy for the determination of quinolones in honey samples, the figures of merit were employed. The limits of quantitation for all analytes were within the range 1.2-56.7 μg kg(-1). The work presented in this paper illustrated the suitability and interesting potential of combining second-order calibration method with second-order analytical instrument for multi-residue analysis in honey samples. PMID:21807221

  17. Vancomycin loaded superparamagnetic MnFe2O4 nanoparticles coated with PEGylated chitosan to enhance antibacterial activity.

    PubMed

    Esmaeili, Akbar; Ghobadianpour, Sepideh

    2016-03-30

    Increasing prevalence of antibiotic-resistant and failed-treatment make more investigations to deal with these problems. Hence new therapeutic approaches for effective treatment are necessary. Ferrite superparamagnetic nanoparticles have potentially antibacterial activity. In this study we prepared MnFe2O4 superparamagnetic nanoparticles as core by precipitation method and used chitosan crosslinked by glutaraldehyde as shell, then modified with PEG to increase stability of particles against RES. Chitosan coating not only improves the properties of ferrit nanoparticles but also has antibacterial activity. FT-IR confirmed this surface modification; XRD and SEM were developed to demonstrate particle size approximately 25nm and characteristics of crystal structure of these nanoparticles. Magnetic properties of nanoparticles were evaluated by VSM. Actual drug loading and releasing were examined by UV-vis spectroscopy method. We employed liquid broth dilution method to assessment antibacterial activity of nanoparticles against microorganisms. Significant antibacterial effect against gram negative bacteria was developed. PMID:26875538

  18. Predicting antibacterial peptides by the concept of Chou's pseudo-amino acid composition and machine learning methods.

    PubMed

    Khosravian, Maede; Faramarzi, Fateme Kazemi; Beigi, Majid Mohammad; Behbahani, Mandana; Mohabatkar, Hassan

    2013-02-01

    Microbial resistance to antibiotics is a rising concern among health care professionals, driving them to search for alternative therapies. In the past few years, antimicrobial peptides (AMPs) have attracted a lot of attention as a substitute for conventional antibiotics. Antimicrobial peptides have a broad spectrum of activity and can act as antibacterial, antifungal, antiviral and sometimes even as anticancer drugs. The antibacterial peptides have little sequence homology, despite common properties. Since there is a need to develop a computational method for predicting the antibacterial peptides, in the present study, we have applied the concept of Chou's pseudo-amino acid composition (PseAAC) and machine learning methods for their classification. Our results demonstrate that using the concept of PseAAC and applying Support Vector Machine (SVM) can provide useful information to predict antibacterial peptides. PMID:22894156

  19. PqsBC, a Condensing Enzyme in the Biosynthesis of the Pseudomonas aeruginosa Quinolone Signal: CRYSTAL STRUCTURE, INHIBITION, AND REACTION MECHANISM.

    PubMed

    Drees, Steffen Lorenz; Li, Chan; Prasetya, Fajar; Saleem, Muhammad; Dreveny, Ingrid; Williams, Paul; Hennecke, Ulrich; Emsley, Jonas; Fetzner, Susanne

    2016-03-25

    Pseudomonas aeruginosaproduces a number of alkylquinolone-type secondary metabolites best known for their antimicrobial effects and involvement in cell-cell communication. In the alkylquinolone biosynthetic pathway, the β-ketoacyl-(acyl carrier protein) synthase III (FabH)-like enzyme PqsBC catalyzes the condensation of octanoyl-coenzyme A and 2-aminobenzoylacetate (2-ABA) to form the signal molecule 2-heptyl-4(1H)-quinolone. PqsBC, a potential drug target, is unique for its heterodimeric arrangement and an active site different from that of canonical FabH-like enzymes. Considering the sequence dissimilarity between the subunits, a key question was how the two subunits are organized with respect to the active site. In this study, the PqsBC structure was determined to a 2 Å resolution, revealing that PqsB and PqsC have a pseudo-2-fold symmetry that unexpectedly mimics the FabH homodimer. PqsC has an active site composed of Cys-129 and His-269, and the surrounding active site cleft is hydrophobic in character and approximately twice the volume of related FabH enzymes that may be a requirement to accommodate the aromatic substrate 2-ABA. From physiological and kinetic studies, we identified 2-aminoacetophenone as a pathway-inherent competitive inhibitor of PqsBC, whose fluorescence properties could be used forin vitrobinding studies. In a time-resolved setup, we demonstrated that the catalytic histidine is not involved in acyl-enzyme formation, but contributes to an acylation-dependent increase in affinity for the second substrate 2-ABA. Introduction of Asn into the PqsC active site led to significant activity toward the desamino substrate analog benzoylacetate, suggesting that the substrate 2-ABA itself supplies the asparagine-equivalent amino function that assists in catalysis. PMID:26811339

  20. Emergence of quinolone resistance and cephalosporin MIC creep in Neisseria gonorrhoeae isolates from a cohort of young men in Kisumu, Kenya, 2002 to 2009.

    PubMed

    Mehta, Supriya D; Maclean, Ian; Ndinya-Achola, Jeckoniah O; Moses, Stephen; Martin, Irene; Ronald, Allan; Agunda, Lawrence; Murugu, Ruth; Bailey, Robert C; Melendez, Johan; Zenilman, Jonathan M

    2011-08-01

    We evaluated antimicrobial resistance in Neisseria gonorrhoeae isolated from men enrolled in a randomized trial of male circumcision to prevent HIV. Urethral specimens from men with discharge were cultured for N. gonorrhoeae. MICs were determined by agar dilution. Clinical and Laboratory Standards Institute (CLSI) criteria defined resistance: penicillin, tetracycline, and azithromycin MICs of ≥2.0 μg/ml; a ciprofloxacin MIC of ≥1.0 μg/ml; and a spectinomycin MIC of ≥128.0 μg/ml. Susceptibility to ceftriaxone and cefixime was shown by an MIC of ≤0.25 μg/ml. Additionally, PCR amplification identified mutations in parC and gyrA genes in selected isolates. From 2002 to 2009, 168 N. gonorrhoeae isolates were obtained from 142 men. Plasmid-mediated penicillin resistance was found in 65%, plasmid-mediated tetracycline resistance in 97%, and 11% were ciprofloxacin resistant (quinolone-resistant N. gonorrhoeae [QRNG]). QRNG appeared in November 2007, increasing from 9.5% in 2007 to 50% in 2009. Resistance was not detected for spectinomycin, cefixime, ceftriaxone, or azithromycin, but MICs of cefixime (P = 0.018), ceftriaxone (P < 0.001), and azithromycin (P = 0.097) increased over time. In a random sample of 51 men, gentamicin MICs were as follows: 4 μg/ml (n = 1), 8 μg/ml (n = 49), and 16 μg/ml (n = 1). QRNG increased rapidly and alternative regimens are required for N. gonorrhoeae treatment in this area. Amid emerging multidrug-resistant N. gonorrhoeae, antimicrobial resistance surveillance is essential for effective drug choice. High levels of plasmid-mediated resistance and increasing MICs for cephalosporins suggest that selective pressure from antibiotic use is a strong driver of resistance emergence. PMID:21606224

  1. Emergence of Quinolone Resistance and Cephalosporin MIC Creep in Neisseria gonorrhoeae Isolates from a Cohort of Young Men in Kisumu, Kenya, 2002 to 2009▿

    PubMed Central

    Mehta, Supriya D.; Maclean, Ian; Ndinya-Achola, Jeckoniah O.; Moses, Stephen; Martin, Irene; Ronald, Allan; Agunda, Lawrence; Murugu, Ruth; Bailey, Robert C.; Melendez, Johan; Zenilman, Jonathan M.

    2011-01-01

    We evaluated antimicrobial resistance in Neisseria gonorrhoeae isolated from men enrolled in a randomized trial of male circumcision to prevent HIV. Urethral specimens from men with discharge were cultured for N. gonorrhoeae. MICs were determined by agar dilution. Clinical and Laboratory Standards Institute (CLSI) criteria defined resistance: penicillin, tetracycline, and azithromycin MICs of ≥2.0 μg/ml; a ciprofloxacin MIC of ≥1.0 μg/ml; and a spectinomycin MIC of ≥128.0 μg/ml. Susceptibility to ceftriaxone and cefixime was shown by an MIC of ≤0.25 μg/ml. Additionally, PCR amplification identified mutations in parC and gyrA genes in selected isolates. From 2002 to 2009, 168 N. gonorrhoeae isolates were obtained from 142 men. Plasmid-mediated penicillin resistance was found in 65%, plasmid-mediated tetracycline resistance in 97%, and 11% were ciprofloxacin resistant (quinolone-resistant N. gonorrhoeae [QRNG]). QRNG appeared in November 2007, increasing from 9.5% in 2007 to 50% in 2009. Resistance was not detected for spectinomycin, cefixime, ceftriaxone, or azithromycin, but MICs of cefixime (P = 0.018), ceftriaxone (P < 0.001), and azithromycin (P = 0.097) increased over time. In a random sample of 51 men, gentamicin MICs were as follows: 4 μg/ml (n = 1), 8 μg/ml (n = 49), and 16 μg/ml (n = 1). QRNG increased rapidly and alternative regimens are required for N. gonorrhoeae treatment in this area. Amid emerging multidrug-resistant N. gonorrhoeae, antimicrobial resistance surveillance is essential for effective drug choice. High levels of plasmid-mediated resistance and increasing MICs for cephalosporins suggest that selective pressure from antibiotic use is a strong driver of resistance emergence. PMID:21606224

  2. The Effect of Ultrafine Process on the Dissolution, Antibacterial Activity, and Cytotoxicity of Coptidis rhizoma

    PubMed Central

    Jiang, Zhen-Yu; Deng, Hai-Ying; Yu, Zhi-Jun; Ni, Jun-Yan; Kang, Si-He

    2016-01-01

    Background: The dosage of herb ultrafine particle (UFP) depended on the increased level of its dissolution, toxicity, and efficacy. Objective: The dissolution, antibacterial activity, and cytotoxicity of Coptidis rhizoma (CR) UFP were compared with those of traditional decoction (TD). Materials and Methods: The dissolution of berberine (BBR) of CR TD and UFP was determined by high-performance liquid chromatography. The antibacterial activity of CR extract was assayed by plate-hole diffusion and broth dilution method; the inhibitory effect of rat serums against bacteria growth was evaluated after orally given CR UFP or TD extract. The cytotoxicity of CR extract was evaluated by 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide assay. Results: The dissolution amount of BBR from CR UFP increased 6–8-folds in comparison to TD at 2 min, the accumulative amount of BBR in both UFP and TD group increased in a time-dependent manner. The minimal inhibitory concentrations and minimal bactericidal concentrations of CR UFP extract decreased to 1/2~1/4 of those of TD extract. The inhibitory effect of rat serums against bacteria growth decreased time-dependently, and no statistical difference was observed between two groups at each time point. The 50% cytotoxic concentrations of UFP extract increased 1.66~1.97 fold than those of TD. Conclusions: The antibacterial activity and cytotoxicity of CR UFP increased in a dissolution-effect manner in vitro, the increased level of cytotoxicity was lower than that of antibacterial activity, and the inhibitory effect of rat serums containing drugs of UFP group did not improve. SUMMARY Ultrafine grinding process caused a rapid increase of BBR dissolution from CR.The antibacterial activity and cytotoxicity of UFP extract in vitro increased in a dissolution-effect manner, but the cytotoxicity increased lower than the antibacterial activity.The antibacterial activity of rat serums of UFP group did not improve in comparison to that of TD group PMID:26941540

  3. Mesoporous TiO2 implants for loading high dosage of antibacterial agent

    NASA Astrophysics Data System (ADS)

    Park, Se Woong; Lee, Donghyun; Choi, Yong Suk; Jeon, Hoon Bong; Lee, Chang-Hoon; Moon, Ji-Hoi; Kwon, Il Keun

    2014-06-01

    We have fabricated mesoporous thin films composed of TiO2 nanoparticles on anodized titanium implant surfaces for loading drugs at high doses. Surface anodization followed by treatment with TiO2 paste leads to the formation of mechanically stable mesoporous thin films with controllable thickness. A series of antibacterial agents (silver nanoparticles, cephalothin, minocycline, and amoxicillin) were loaded into the mesoporous thin films and their antibacterial activities were evaluated against five bacterial species including three oral pathogens. Additionally, two agents (silver nanoparticles and minocycline) were loaded together on the thin film and tested for antibacterial effectiveness. The combination of silver nanoparticles and minocycline was found to display a wide range of effectiveness against all tested bacteria.

  4. Antibacterial Activity of Leaf Extracts of Baeckea frutescens against Methicillin-Resistant Staphylococcus aureus

    PubMed Central

    Razmavar, Somayeh; Abdulla, Mahmood Ameen; Ismail, Salmah Binti; Hassandarvish, Pouya

    2014-01-01

    This study was based on screening antibacterial activity of the ethanol extract of Baeckea frutescens L. against MRSA clinical isolates, analyzes the potential antibacterial compound, and assesses the cytotoxicity effect of the extract in tissue culture. Leaves of Baeckea frutescens L. were shade dried, powdered, and extracted using solvent ethanol. Preliminary phytochemical screening of the crude extracts revealed the presence of alkaloids, flavonoids, steroids, terpenoids, phenols, and carbohydrates. The presence of these bioactive constituents is related to the antibacterial activity of the plant. Disc diffusion method revealed a high degree of activity against microorganisms. The results confirm that Baeckea frutescens L. can be used as a source of drugs to fight infections caused by susceptible bacteria. PMID:25028658

  5. Fluoroquinolone interactions with Mycobacterium tuberculosis gyrase: Enhancing drug activity against wild-type and resistant gyrase.

    PubMed

    Aldred, Katie J; Blower, Tim R; Kerns, Robert J; Berger, James M; Osheroff, Neil

    2016-02-16

    Mycobacterium tuberculosis is a significant source of global morbidity and mortality. Moxifloxacin and other fluoroquinolones are important therapeutic agents for the treatment of tuberculosis, particularly multidrug-resistant infections. To guide the development of new quinolone-based agents, it is critical to understand the basis of drug action against M. tuberculosis gyrase and how mutations in the enzyme cause resistance. Therefore, we characterized interactions of fluoroquinolones and related drugs with WT gyrase and enzymes carrying mutations at GyrA(A90) and GyrA(D94). M. tuberculosis gyrase lacks a conserved serine that anchors a water-metal ion bridge that is critical for quinolone interactions with other bacterial type II topoisomerases. Despite the fact that the serine is replaced by an alanine (i.e., GyrA(A90)) in M. tuberculosis gyrase, the bridge still forms and plays a functional role in mediating quinolone-gyrase interactions. Clinically relevant mutations at GyrA(A90) and GyrA(D94) cause quinolone resistance by disrupting the bridge-enzyme interaction, thereby decreasing drug affinity. Fluoroquinolone activity against WT and resistant enzymes is enhanced by the introduction of specific groups at the C7 and C8 positions. By dissecting fluoroquinolone-enzyme interactions, we determined that an 8-methyl-moxifloxacin derivative induces high levels of stable cleavage complexes with WT gyrase and two common resistant enzymes, GyrA(A90V) and GyrA(D94G). 8-Methyl-moxifloxacin was more potent than moxifloxacin against WT M. tuberculosis gyrase and displayed higher activity against the mutant enzymes than moxifloxacin did against WT gyrase. This chemical biology approach to defining drug-enzyme interactions has the potential to identify novel drugs with improved activity against tuberculosis. PMID:26792518

  6. Synthesis, spectral characterization and antimicrobial activity of substituted thiazolyl derivatives of 2-quinolones.

    PubMed

    Katagi, M S; Bolakatti, G S; Badiger, A M; Satyanarayana, D; Mamledesai, S N; Sujatha, M L

    2013-02-01

    A series of new 3-(2-substituted amino/substituted hydrazino-1,3-thiazol-4-yl)-4-hydroxy-1-methyl/phenylquinolin-2 (1H)-one hydroiodide 3a-3f and 4a-4f derivatives were prepared by heating 3-Acetyl-4-hydroxy-1-methyl/phenyl quinolin-2 (1H)-one 2a-2b with substituted thiourea and substituted thiosemicarbazide in presence of iodine in n-butanol. The title compounds were characterized on the basis of IR, 1H NMR, 13C NMR and Mass spectral (MS) studies. Further title compounds were evaluated for antibacterial and antifungal by Agar diffusion assay method where as antitubercular activity by Micro-plate Alamar Blue Assay (MABA). Among 12 synthesized novel compounds 3a, 3b, 4d exhibited promising antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa. 3a, 3b, 3e, 4d, 4e showed good antifungal activity against Candida albicans and Aspergillus niger. 3a, 3d, 4d showed good antitubercular activity against Mycobacterium tuberculosis H37Rv strain. PMID:23427049

  7. Polymeric micellar nanoplatforms for Fenton reaction as a new class of antibacterial agents.

    PubMed

    Park, Seong-Cheol; Kim, Nam-Hong; Yang, Wonseok; Nah, Jae-Woon; Jang, Mi-Kyeong; Lee, Dongwon

    2016-01-10

    Reactive oxygen species (ROS) produced by host phagocytes exert antibacterial action against a variety of pathogens and ROS-induced oxidative stress is the governing mechanism for the antibacterial activity of major bactericidal antibiotics. In particular, hydroxyl radical is a strong and nonselective oxidant which can damage biomolecules such as DNA, proteins and lipids. Ferrous ion is known to convert mild oxidant hydrogen peroxide (H2O2) into highly reactive and toxic hydroxyl radicals, referred to as Fenton reaction. Herein, we report a new class of antibacterial agents based on Fenton reaction-performing nanostructures, composed of H2O2-generating polymer (PCAE) and iron-containing ferrocene. Amphiphilic PCAE was designed to incorporate H2O2-generating cinnamaldehyde through acid-cleavable linkages and self-assemble to form thermodynamically stable micelles which could encapsulate ferrocene in their hydrophobic core. All the experiments in vitro display that ferrocene-loaded PCAE micelles produce hydroxyl radicals to kill Escherichia coli and Pseudomonas aeruginosa through membrane damages. Intraperitoneally injected ferrocene-loaded PCAE micelles significantly reduced the lung damages and therefore increased the survival rate of mice infected with drug resistant P. aeruginosa. Given their potent antibacterial activity, ferrocene-loaded PCAE micelles hold great potential as a new class of ROS-manipulating antibacterial agents. PMID:26639177

  8. Toxicity and antibacterial assessment of chitosancoated silver nanoparticles on human pathogens and macrophage cells

    PubMed Central

    Jena, Prajna; Mohanty, Soumitra; Mallick, Rojee; Jacob, Biju; Sonawane, Avinash

    2012-01-01

    Background Pathogenic bacteria are able to develop various strategies to counteract the bactericidal action of antibiotics. Silver nanoparticles (AgNPs) have emerged as a potential alternative to conventional antibiotics because of their potent antimicrobial properties. The purpose of this study was to synthesize chitosan-stabilized AgNPs (CS-AgNPs) and test for their cytotoxic, genotoxic, macrophage cell uptake, antibacterial, and antibiofilm activities. Methods AgNPs were synthesized using chitosan as both a stabilizing and a reducing agent. Antibacterial activity was determined by colony-forming unit assay and scanning electron microscopy. Genotoxic and cytotoxic activity were determined by DNA fragmentation, comet, and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assays. Cellular uptake and intracellular antibacterial activity were tested on macrophages. Results CS-AgNPs exhibited potent antibacterial activity against different human pathogens and also impeded bacterial biofilm formation. Scanning electron microscopy analysis indicated that CS-AgNPs kill bacteria by disrupting the cell membrane. CS-AgNPs showed no significant cytotoxic or DNA damage effect on macrophages at the bactericidal dose. Propidium iodide staining indicated active endocytosis of CS-AgNPs resulting in reduced intracellular bacterial survival in macrophages. Conclusion The present study concludes that at a specific dose, chitosan-based AgNPs kill bacteria without harming the host cells, thus representing a potential template for the design of antibacterial agents to decrease bacterial colonization and to overcome the problem of drug resistance. PMID:22619529

  9. Facile biofunctionalization of silver nanoparticles for enhanced antibacterial properties, endotoxin removal, and biofilm control

    PubMed Central

    Lambadi, Paramesh Ramulu; Sharma, Tarun Kumar; Kumar, Piyush; Vasnani, Priyanka; Thalluri, Sitaramanjaneya Mouli; Bisht, Neha; Pathania, Ranjana; Navani, Naveen Kumar

    2015-01-01

    Infectious diseases cause a huge burden on healthcare systems worldwide. Pathogenic bacteria establish infection by developing antibiotic resistance and modulating the host’s immune system, whereas opportunistic pathogens like Pseudomonas aeruginosa adapt to adverse conditions owing to their ability to form biofilms. In the present study, silver nanoparticles were biofunctionalized with polymyxin B, an antibacterial peptide using a facile method. The biofunctionalized nanoparticles (polymyxin B-capped silver nanoparticles, PBSNPs) were assessed for antibacterial activity against multiple drug-resistant clinical strain Vibrio fluvialis and nosocomial pathogen P. aeruginosa. The results of antibacterial assay revealed that PBSNPs had an approximately 3-fold higher effect than the citrate-capped nanoparticles (CSNPs). Morphological damage to the cell membrane was followed by scanning electron microscopy, testifying PBSNPs to be more potent in controlling the bacterial growth as compared with CSNPs. The bactericidal effect of PBSNPs was further confirmed by Live/Dead staining assays. Apart from the antibacterial activity, the biofunctionalized nanoparticles were found to resist biofilm formation. Electroplating of PBSNPs onto stainless steel surgical blades retained the antibacterial activity against P. aeruginosa. Further, the affinity of polymyxin for endotoxin was exploited for its removal using PBSNPs. It was found that the prepared nanoparticles removed 97% of the endotoxin from the solution. Such multifarious uses of metal nanoparticles are an attractive means of enhancing the potency of antimicrobial agents to control infections. PMID:25834431

  10. Antibacterial barbituric acid analogues inspired from natural 3-acyltetramic acids; synthesis, tautomerism and structure and physicochemical property-antibacterial activity relationships.

    PubMed

    Jeong, Yong-Chul; Moloney, Mark G

    2015-01-01

    The synthesis, tautomerism and antibacterial activity of novel barbiturates is reported. In particular, 3-acyl and 3-carboxamidobarbiturates exhibited antibacterial activity, against susceptible and some resistant Gram-positive strains of particular interest is that these systems possess amenable molecular weight, rotatable bonds and number of proton-donors/acceptors for drug design as well as less lipophilic character, with physicochemical properties and ionic states that are similar to current antibiotic agents for oral and injectable use. Unfortunately, the reduction of plasma protein affinity by the barbituric core is not sufficient to achieve activity in vivo. Further optimization to reduce plasma protein affinity and/or elevate antibiotic potency is therefore required, but we believe that these systems offer unusual opportunities for antibiotic drug discovery. PMID:25710842

  11. Overcoming scientific and structural bottlenecks in antibacterial discovery and development

    PubMed Central

    2014-01-01

    Antibiotic resistance is becoming an increasing threat, with too few novel antibiotics coming to market to replace those lost due to resistance development. Efforts by the pharmaceutical industry to screen for and design novel antibacterials have not been successful, with several companies minimizing or closing down their antibacterial research units, leading to a loss of skills and know-how. At the same time, antibiotic innovation in academia is not filling the void due to misaligned incentive structures and lack of vital knowledge of drug discovery. The scientific and structural difficulties in discovering new antibiotics have only begun to be appreciated in the latest years. Part of the problem has been a paradigm shift within both industry and academia to focus on ‘rational’ drug development with an emphasis on single targets and high-throughput screening of large chemical libraries, which may not be suited to target bacteria. The very particular aspects of ‘targeting an organism inside another organism’ have not been given enough attention. In this paper, researcher interviews have complemented literature studies to delve deeper into the specifics of the different scientific and structural barriers, and some potential solutions are offered. PMID:24646118

  12. Simultaneous removal and degradation characteristics of sulfonamide, tetracycline, and quinolone antibiotics by laccase-mediated oxidation coupled with soil adsorption.

    PubMed

    Ding, Huijun; Wu, Yixiao; Zou, Binchun; Lou, Qian; Zhang, Weihao; Zhong, Jiayou; Lu, Lei; Dai, Guofei

    2016-04-15

    The uses of laccase in the degradation and removal of antibiotics have recently been reported because of the high efficiency and environmental friendliness of laccase. However, these removal studies mostly refer to a limited number of antibiotics. In this study, soil adsorption was introduced into the laccase-oxidation system to assist the simultaneous removal of 14 kinds of sulfonamide, tetracycline, and quinolone antibiotics, which differed in structures and chemical properties. The complementary effects of laccase-mediated oxidation and soil adsorption enabled the simultaneous removal. Removal characteristics were determined by a comprehensive consideration of the separate optimum conditions for laccase oxidation and soil adsorption removal experiments. With concentrations of laccase, syringaldehyde (SA), and soil of 0.5mg/mL, 0.5mmol/L, and 50g/L, respectively, and at pH 6 and 25°C, the removal rates of each antibiotic exceeded 70% in 15min and were close to 100% in 180min. Sulfonamide antibiotics (SAs) were removed mainly by laccase oxidation and quinolone antibiotics (QUs) mainly by soil adsorption. Tetracycline antibiotics (TCs) were removed by both treatments in the coupled system, but laccase oxidation dominated. Electrostatic adsorption was speculated to be one of the adsorption mechanisms in soil adsorption with QUs and TCs. PMID:26826938

  13. Identification of the main quinolone resistance determinant in Campylobacter jejuni and Campylobacter coli by MAMA-DEG PCR.

    PubMed

    Hormeño, Lorena; Palomo, Gonzalo; Ugarte-Ruiz, María; Porrero, M Concepción; Borge, Carmen; Vadillo, Santiago; Píriz, Segundo; Domínguez, Lucas; Campos, Maria J; Quesada, Alberto

    2016-03-01

    Among zoonotic diseases, campylobacteriosis stands out as the major bacterial infection producing human gastroenteritis. Antimicrobial therapy, only recommended in critical cases, is challenged by resistance mechanisms that should be unambiguously detected for achievement of effective treatments. Quinolone (ciprofloxacin) resistance of Campylobacter jejuni and Campylobacter coli, the 2 main Campylobacter detected in humans, is conferred by the mutation gyrA C-257-T, which can be genotyped by several methods that require a previous identification of the pathogen species to circumvent the sequence polymorphism of the gene. A multiplex PCR, based on degenerated oligonucleotides, has been designed for unambiguous identification of the quinolone resistance determinant in Campylobacter spp. isolates. The method was verified with 249 Campylobacter strains isolated from humans (141 isolates) and from the 3 most important animal sources for this zoonosis: poultry (34 isolates), swine (38 isolates), and cattle (36 isolates). High resistance to ciprofloxacin, MIC above 4μg/mL, linked to the mutated genotype predicted by MAMA-DEG PCR (mismatch amplification mutation assay PCR with degenerated primers) was found frequently among isolates from the different hosts. PMID:26658311

  14. [Multi-residue determination of 11 quinolones in chicken muscle by high performance liquid chromatography with fluorescence detection].

    PubMed

    Lin, Baoyin

    2009-03-01

    A high performance liquid chromatographic (HPLC) method with fluorescence detection was developed for the simultaneous determination of 11 quinolones (QNs) (norfloxacin, ofloxacin, ciprofloxacin, pefloxacin, lomefloxacin, danofloxacin, enrofloxacin, sarafloxacin, difloxacin, oxolinic acid and flumequine) residues in chicken muscle. The chicken muscle samples were extracted by 10% trichioroacetic acid/acetonitrile (7:3, v/v) twice, diluted and cleaned up by a reversed-phase solid-phase extraction (SPE) cartridge. The QNs were separated on a reversed-phase C18 column (Hypersil BDS-C18) with mobile phase gradient elution (acetonitrile and water as mobile phases) and detected by a fluorescence detector with a wavelength program. The linear ranges of quinolone calibrations were 5-1200 microg/L in chicken muscle with the correlation coefficients more than 0.998. The recoveries for chicken muscle fortified with 11 QNs at three levels were 56%-119% with acceptable intra-batch relative standard deviations (RSD) (0.4%-16.1%) and inter-batch RSD (1.4%-23.0%). The limits of detection (LOD) and limits of quantification (LOQ) were 1-23 microg/kg and 4-40 kg/kg for the 11 QNs, respectively. The sensitivity meets the quantification requirements for the residue analysis. PMID:19626850

  15. Molecular characterization of quinolone resistance mechanisms and extended-spectrum β-lactamase production in Escherichia coli isolated from dogs.

    PubMed

    Meireles, D; Leite-Martins, L; Bessa, L J; Cunha, S; Fernandes, R; de Matos, A; Manaia, C M; Martins da Costa, P

    2015-08-01

    The increasing prevalence of antimicrobial resistances is now a worldwide problem. Investigating the mechanisms by which pets harboring resistant strains may receive and/or transfer resistance determinants is essential to better understanding how owners and pets can interact safely. Here, we characterized the genetic determinants conferring resistance to β-lactams and quinolones in 38 multidrug-resistant Escherichia coli isolated from fecal samples of dogs, through PCR and sequencing. The most frequent genotype included the β-lactamase groups TEM (n=5), and both TEM+CTX-M-1 (n=5). Within the CTX-M group, we identified the genes CTX-M-32, CTX-M-1, CTX-M-15, CTX-M-55/79, CTX-M-14 and CTX-M-2/44. Thirty isolates resistant to ciprofloxacin presented two mutations in the gyrA gene and one or two mutations in the parC gene. A mutation in gyrA (reported here for the first time), due to a transversion and transition (TCG→GTG) originating a substitution of a serine by a valine in position 83 was also detected. The plasmid-encoded quinolone resistance gene, qnrs1, was detected in three isolates. Dogs can be a reservoir of genetic determinants conferring antimicrobial resistance and thus may play an important role in the spread of antimicrobial resistance to humans and other co-habitant animals. PMID:25999092

  16. Detection of gyrA Mutations in Quinolone-Resistant Salmonella enterica by Denaturing High-Performance Liquid Chromatography

    PubMed Central

    Eaves, Deborah J.; Liebana, Ernesto; Woodward, Martin J.; Piddock, Laura J. V.

    2002-01-01

    Denaturing high-performance liquid chromatography (DHPLC) was evaluated as a rapid screening and identification method for DNA sequence variation detection in the quinolone resistance-determining region of gyrA from Salmonella serovars. A total of 203 isolates of Salmonella were screened using this method. DHPLC analysis of 14 isolates representing each type of novel or multiple mutations and the wild type were compared with LightCycler-based PCR-gyrA hybridization mutation assay (GAMA) and single-strand conformational polymorphism (SSCP) analyses. The 14 isolates gave seven different SSCP patterns, and LightCycler detected four different mutations. DHPLC detected 11 DNA sequence variants at eight different codons, including those detected by LightCycler or SSCP. One of these mutations was silent. Five isolates contained multiple mutations, and four of these could be distinguished from the composite sequence variants by their DHPLC profile. Seven novel mutations were identified at five different loci not previously described in quinolone-resistant salmonella. DHPLC analysis proved advantageous for the detection of novel and multiple mutations. DHPLC also provides a rapid, high-throughput alternative to LightCycler and SSCP for screening frequently occurring mutations. PMID:12409384

  17. Phylogenetic groups, virulence genes and quinolone resistance of integron-bearing Escherichia coli strains isolated from a wastewater treatment plant.

    PubMed

    Mokracka, Joanna; Koczura, Ryszard; Jab?o?ska, Lucyna; Kaznowski, Adam

    2011-05-01

    We investigated phylogenetic affiliation, occurrence of virulence genes and quinolone resistance in 109 integron-containing strains of Escherichia coli isolated from a wastewater treatment plant. Selection for integron-bearing strains caused a shift toward phylogroup D, which was most numerous, followed by A, B1 and B2. Phylogroups D and B2, both of which are reported to include virulent extraintestinal pathotypes, made up 50.5% of all isolates and were present in every stage of wastewater treatment, including final effluent. Diarrheagenic pathotypes made up 21% of the strains. The average virulence factor genes score was low (1.40) and the range was from 0 to 5. Quinolone and fluoroquinolone resistance was observed in 56.0% and 50.4% of the strains, respectively; however, it was not associated with virulence factor score. Although the average virulence factor score was low, 17.4% of strains had three and more virulence genes. They were isolated mostly from raw sewage, but 30% of them were cultured from final effluent. Release of multiresistant integron-bearing E. coli strains with virulence traits into the environment may create potential threat and be of public health concern. PMID:21293926

  18. A rapid microbial inhibition-based screening strategy for fluoroquinolone and quinolone residues in foods of animal origin.

    PubMed

    Ashwin, Helen; Stead, Sara; Caldow, Marianne; Sharman, Matthew; Stark, Jacques; de Rijk, Angelique; Keely, Brendan J

    2009-04-01

    A rapid, high-throughput antimicrobial screening assay for the detection of fluoroquinolone and 4-quinolone residues in foods of animal origin has been developed in ampoule format. The assay employs a single Escherichia coli species sensitive to those Gram-negative inhibitiory antimicrobial compounds and is presented in a comparable format to the existing commercially available Premi Test and Delvotest ampoule-based microbial inhibition tests (DSM, Delft, The Netherlands). In the novel E. coli assay the microorganism, in vegetative state, is inoculated into a nutrient agar pellet containing a pH sensitive acid-base indicator dye. A simple extraction protocol that is selective for fluoroquinolone and quinolone compounds was developed to recover, cleanup and concentrate the target analyte(s) from a variety of tissue types and matrices prior to screening analysis. The method detected 16 target compounds at concentrations equal to or below the maximum residue limits (where applicable). The method has been validated using the prototype assay in accordance with the 2002/657/EC guidelines for the validation of qualitative screening assays. False positive and false negative responses rates for the procedure have been determined as less than 5%. The stability of a selection of representative target analytes has been demonstrated for a 20-week period under a variety of storage conditions both in tissue and in extract. PMID:19286036

  19. QapR (PA5506) Represses an Operon That Negatively Affects the Pseudomonas Quinolone Signal in Pseudomonas aeruginosa

    PubMed Central

    Tipton, Kyle A.; Coleman, James P.

    2013-01-01

    Pseudomonas aeruginosa is a Gram-negative, opportunistic pathogen that can cause disease in varied sites within the human body and is a significant source of morbidity and mortality in those afflicted with cystic fibrosis. P. aeruginosa is able to coordinate group behaviors, such as virulence factor production, through the process of cell-to-cell signaling. There are three intercellular signaling systems employed by P. aeruginosa, and one of these systems utilizes the small molecule 2-heptyl-3-hydroxy-4-quinolone (Pseudomonas quinolone signal [PQS]). PQS is required for virulence in multiple infection models and has been found in the lungs of cystic fibrosis patients colonized by P. aeruginosa. In this study, we have identified an RpiR family transcriptional regulator, QapR, which is an autoregulatory repressor. We found that mutation of qapR caused overexpression of the qapR operon. We characterized the qapR operon to show that it contains genes qapR, PA5507, PA5508, and PA5509 and that QapR directly controls the transcription of these genes in a negative manner. We also show that derepression of this operon greatly reduces PQS concentration in P. aeruginosa. Our results suggest that qapR affects PQS concentration by repressing an enzymatic pathway that acts on PQS or a PQS precursor to lower the PQS concentration. We believe that this operon comprises a novel mechanism to regulate PQS concentration in P. aeruginosa. PMID:23708133

  20. High-frequency transposition for determining antibacterial mode of action.

    PubMed

    Wang, Hao; Claveau, David; Vaillancourt, John P; Roemer, Terry; Meredith, Timothy C

    2011-10-01

    Connecting bacterial growth inhibitors to molecular targets at the whole-cell level is a major impediment to antibacterial development. Herein we report the design of a highly efficient and versatile bacteriophage-based mariner transposon delivery system in Staphylococcus aureus for determining inhibitor mode of action. Using bacteriophage-mediated delivery of concatameric minitransposon cassettes, we generated nonclonal transposant libraries with genome-wide insertion-site coverage in either laboratory or methicillin-resistant strain backgrounds and screened for drug resistance in situ on a single agar plate in one step. A gradient of gene-target expression levels, along with a correspondingly diverse assortment of drug-resistant phenotypes, was achieved by fitting the transposon cassette with a suite of outward-facing promoters. Using a panel of antibiotics, we demonstrate the ability to unveil not only an inhibitor's molecular target but also its route of cellular entry, efflux susceptibility and other off-target resistance mechanisms. PMID:21892185

  1. Antibacterial activity of polyphenols of garcinia indica.

    PubMed

    Lakshmi, C; Kumar, K Akshaya; Dennis, T J; Kumar, T S S P N S Sanath

    2011-07-01

    The aim of present work is to study the antibacterial activity of polyphenols isolated from the ethyl acetate soluble of methanol extract of stem bark of Garcinia indica against Staphylococcus aureus, Salmonella typhi and Escherichia coli by paper disc method. The results showed good antibacterial activity against S. aureus at higher concentrations, moderate at lower concentrations, against S. typhi moderate at higher concentrations but no activity against E. coli even at higher concentration for flavononylflavone. With proauthocyanin S. Aureus, S. Typhi and E. coli showed good antibacterial activity at higher concentration only. PMID:22707838

  2. Synthesis and Antibacterial Activities of Yanglingmycin Analogues.

    PubMed

    Li, Long-Bo; Dan, Wen-Jia; Tan, Fang-Fang; Cui, Li-Hui; Yuan, Zhi-Peng; Wu, Wen-Jun; Zhang, Ji-Wen

    2014-10-30

    The synthesis of Yanglingmycin and its enantiomer, along with eighteen Yanglingmycin analogues is reported. The structures were confirmed mainly by analyses of NMR spectral data. Antibacterial activity assays showed that Yanglingmycin and some of its analogues exhibited significant antibacterial activities against two important agricultural pathogenic bacteria, Ralstonia solanacearum and Pseudomonas syringae pv. actinidiae, with MIC values ranging from 3.91 to 15.62 μg/mL. The antibacterial activities exhibited by Yanglingmycin and its analogues are promising, suggesting potential in the development of compounds for novel bactericides. PMID:25355464

  3. Synthesis and antibacterial activities of Yanglingmycin analogues.

    PubMed

    Li, Long-Bo; Dan, Wen-Jia; Tan, Fang-Fang; Cui, Li-Hui; Yuan, Zhi-Peng; Wu, Wen-Jun; Zhang, Ji-Wen

    2015-01-01

    The synthesis of Yanglingmycin and its enantiomer, along with eighteen Yanglingmycin analogues is reported. The structures were confirmed mainly by analyses of NMR spectral data. Antibacterial activity assays showed that Yanglingmycin and some of its analogues exhibited significant antibacterial activities against two important agricultural pathogenic bacteria, Ralstonia solanacearum and Pseudomonas syringae pv. actinidiae, with minimum inhibitory concentration (MIC) values ranging from 3.91 to 15.62 µg/mL. The antibacterial activities exhibited by Yanglingmycin and its analogues are promising, suggesting potential in the development of compounds for novel bactericides. PMID:25743192

  4. Toward bioactive yet antibacterial surfaces.

    PubMed

    Sukhorukova, I V; Sheveyko, A N; Kiryukhantsev-Korneev, Ph V; Zhitnyak, I Y; Gloushankova, N A; Denisenko, E A; Filippovich, S Yu; Ignatov, S G; Shtansky, D V

    2015-11-01

    The fabrication of antibacterial yet biocompatible and bioactive surfaces is a challenge that biological and biomedical community has faced for many years, while no "dream material" has been developed so far. The primary goal of this study was to establish an optimal range of Ag concentration and its state of agglomeration in bioactive nanocomposite TiCaPCON films which would provide a strong bactericidal effect without compromising the material biocompatibility and bioactivity. To obtain samples with different Ag content and redistribution, two different methods were employed: (i) TiCaPCON films deposition by magnetron sputtering of composite Ti?0.5-Ca3(??4)2 target followed by Ag(+) ion implantation and (ii) Ag-doped TiCaPCON films obtained by co-sputtering of composite Ti?0.5-Ca3(??4)2 and Ag targets. In order to reveal the antibacterial role of Ag nanoparticles and Ag(+) ions, both separate and in synergy, part of the samples from the first and second groups was subjected to additional ion etching to remove an Ag rich surface layer heavily populated with Ag nanoparticles. All resultant films were characterized with respect to surface morphology, chemical composition, surface roughness, wettability, and Ag(+) ion release. The antibacterial and antifungal effects of the Ag-doped TiCaPCON films were evaluated against clinically isolated Escherichia coli O78 (E. coli) and Neurospora crassa wt-987 spores. The influence of the surface chemistry on spreading, proliferation, and early stages of MC3T3-E1 osteoblastic cell differentiation was also studied. Our data demonstrated that under optimal conditions in terms of Ag content and agglomeration, the Ag-doped TiCaPCON films are highly efficient against E. coli bacteria and, at the same time, provide good adhesion, spreading, proliferation and differentiation of osteoblastic cells which reflect high level of biocompatibility and bioactivity of the films. The influence of Ag(+) ions and nanoparticles on the MC3T3-E1 osteoblastic cells and E. coli bacteria is also discussed. PMID:26255161

  5. Drug-induced nail disorders.

    PubMed

    2014-07-01

    Nail disorders are defined according to their appearance and the part of the nail affected: the nail plate, the tissues that support or hold the nail plate in place, or the lunula. The consequences of most nail disorders are purely cosmetic. Other disorders, such as ingrown nails, inflammation, erythema, abscesses or tumours, cause functional impairment or pain. The appearance of the lesions is rarely indicative of their cause. Possible causes include physiological changes, local disorders or trauma, systemic conditions, toxic substances and drugs. Most drug-induced nail disorders resolve after discontinuation of the drug, although complete resolution sometimes takes several years. Drugs appear to induce nail disorders through a variety of mechanisms. Some drugs affect the nail matrix epithelium, the nail bed or the nail folds. Some alter nail colour. Other drugs induce photosensitivity. Yet others affect the blood supply to the nail unit. Nail abnormalities are common during treatment with certain cytotoxic drugs: taxanes, anthracyclines, fluorouracil, EGFR, tyrosine kinase inhibitors, etc. Some drugs are associated with a risk of serious and painful lesions, such as abscesses. When these disorders affect quality of life, the benefits of withdrawing the drug must be weighed against the severity of the condition being treated and the drug's efficacy, taking into account the harm-benefit balance of other options. Various anti-infective drugs, including tetracyclines, quinolones, clofazimine and zidovudine, cause the nail plate to detach from the nail bed after exposure to light, or cause nail discoloration. Psoralens and retinoids can also have the same effects. PMID:25162091

  6. Antibacterial Effects and Biocompatibility of Titania Nanotubes with Octenidine Dihydrochloride/Poly(lactic-co-glycolic acid)

    PubMed Central

    Xu, Zhiqiang; Lai, Yingzhen; Wu, Dong; Huang, Wenxiu; Huang, Sijia; Zhou, Lin; Chen, Jiang

    2015-01-01

    Titanium (Ti) implants with long-term antibacterial ability and good biocompatibility are highly desirable materials that can be used to prevent implant-associated infections. In this study, titania nanotubes (TNTs) were synthesized on Ti surfaces through electrochemical anodization. Octenidine dihydrochloride (OCT)/poly(lactic-co-glycolic acid) (PLGA) was infiltrated into TNTs using a simple solvent-casting technique. OCT/PLGA-TNTs demonstrated sustained drug release and maintained the characteristic hollow structures of TNTs. TNTs (200 nm in diameter) alone exhibited slight antibacterial effect and good osteogenic activity but also evidently impaired adhesion and proliferation of bone marrow mesenchymal stem cells (BMSCs). OCT/PLGA-TNTs (100 nm in diameter) supported BMSC adhesion and proliferation and showed good osteogenesis-inducing ability. OCT/PLGA-TNTs also exhibited good long-term antibacterial ability within the observation period of 7 d. The synthesized drug carrier with relatively long-term antibacterial ability and enhanced excellent biocompatibility demonstrated significant potential in bone implant applications. PMID:26090449

  7. Emergence of Plasmid-Mediated Quinolone Resistance among Non-Typhi Salmonella enterica Isolates from Humans in the United States ▿

    PubMed Central

    Sjölund-Karlsson, Maria; Folster, Jason P.; Pecic, Gary; Joyce, Kevin; Medalla, Felicita; Rickert, Regan; Whichard, Jean M.

    2009-01-01

    Plasmid-mediated quinolone resistance determinants are emerging among gram-negative pathogens. Here we report results of a retrospective study investigating the prevalence of aac(6′)-Ib-cr, qepA, and qnr genes among 19,010 human isolates of non-Typhi Salmonella enterica collected in the United States from 1996 to 2006. PMID:19223618

  8. Drug-induced tendinopathy: from physiology to clinical applications.

    PubMed

    Kirchgesner, Thomas; Larbi, Ahmed; Omoumi, Patrick; Malghem, Jacques; Zamali, Nadia; Manelfe, Julien; Lecouvet, Frédéric; Vande Berg, Bruno; Djebbar, Sahlya; Dallaudière, Benjamin

    2014-12-01

    Drug-induced tendon toxicity is rare but often underestimated. To date, four main drug classes have been incriminated in tendinopathies. Quinolones and long-term glucocorticoids are the most widely known, but statins and aromatase inhibitors can also induce tendon damage. The specific pathophysiological mechanisms responsible for drug-induced tendinopathies remain unknown. Proven risk factors have been identified, such as age older than 60 years, pre-existing tendinopathy, and potentiation of toxic effects when several drug classes are used in combination. Mean time to symptom onset varies from a few days with quinolones to several months with statins and several years for long-term glucocorticoid therapy. The most common sites of involvement are the lower limb tendons, most notably the body of the Achilles tendon. The first part of this review discusses tendon anatomy and the pathophysiology and radiological manifestations of tendinopathies. The second part provides details on the main characteristics of each of the drugs classes associated with tendon toxicity. PMID:24962977

  9. Antibacterial and antifungal activities of Angiopteris evecta.

    PubMed

    Khan, M R; Omoloso, A D

    2008-07-01

    The leaves, stem bark, stem heart wood, root and tubers of Angiopteris evecta were successively extracted with petrol, dichloromethane, ethyl acetate, butanol and methanol. All the fractions exhibited a wider spectrum of antibacterial activity. The dichloromethane and ethyl acetate fractions of the leaves and stem bark were particularly good and were the only fractions exhibiting antifungal activity. All fractions of the tuber with the exception of petrol, exhibited very good antibacterial activity. PMID:18505704

  10. Antibacterial Activity of Geminized Amphiphilic Cationic Homopolymers.

    PubMed

    Wang, Hui; Shi, Xuefeng; Yu, Danfeng; Zhang, Jian; Yang, Guang; Cui, Yingxian; Sun, Keji; Wang, Jinben; Yan, Haike

    2015-12-22

    The current study is aimed at investigating the effect of cationic charge density and hydrophobicity on the antibacterial and hemolytic activities. Two kinds of cationic surfmers, containing single or double hydrophobic tails (octyl chains or benzyl groups), and the corresponding homopolymers were synthesized. The antimicrobial activity of these candidate antibacterials was studied by microbial growth inhibition assays against Escherichia coli, and hemolysis activity was carried out using human red blood cells. It was interestingly found that the homopolymers were much more effective in antibacterial property than their corresponding monomers. Furthermore, the geminized homopolymers had significantly higher antibacterial activity than that of their counterparts but with single amphiphilic side chains in each repeated unit. Geminized homopolymers, with high positive charge density and moderate hydrophobicity (such as benzyl groups), combine both advantages of efficient antibacterial property and prominently high selectivity. To further explain the antibacterial performance of the novel polymer series, the molecular interaction mechanism is proposed according to experimental data which shows that these specimens are likely to kill microbes by disrupting bacterial membranes, leading them unlikely to induce resistance. PMID:26606647

  11. Antibacterial Attributes of Apigenin, Isolated from Portulaca oleracea L.

    PubMed Central

    Nayaka, Hanumantappa B.; Londonkar, Ramesh L.; Umesh, Madire K.; Tukappa, Asha

    2014-01-01

    The flavonoid apigenin was isolated from aerial part of P. oleracea L. The dried sample of plant was powdered and subjected to soxhlet extractor by adding 80 mL of ethanol : water (70 : 30). The extract was centrifuged at 11000 rpm for 30 min; supernatant was taken for further use. The fraction was concentrated and subjected to PTLC. The Rf value of isolated apigenin was calculated (0.82). Purified material was also subjected to its IR spectra, LC-MS, NMR, and HPLC for structural elucidation. The apigenin so-obtained was subjected to antibacterial activity on five pathogenic bacterial strains like Pseudomonas aeruginosa, Salmonella typhimurium, Proteus mirabilis, Klebsiella pneumoniae and Enterobacter aerogenes; among all the bacterial strains, Salmonella typhimurium (17.36 ± 0.18) and Proteus mirabilis (19.12 ± 0.01) have shown maximum diameter of inhibition zone for flavonoid and remaining bacterial strains have shown moderate diameter of inhibition zone when compared with control values 14.56 ± 0.21 and 11.68 ± 0.13, respectively. The minimum inhibitory concentration (MIC) of the flavonoid isolated from P. oleracea L. was tested at the concentration ranging from undiluted sample to 10 mg per mL of concentration. The minimum inhibition concentration (MIC) for the flavonoid for all tested bacterial strains was found to be >4 mg per mL. Hence, the apigenin has antibacterial property and can be used to develop antibacterial drugs. PMID:26904730

  12. Investigations to the Antibacterial Mechanism of Action of Kendomycin

    PubMed Central

    A. Elnakady, Yasser; Chatterjee, Indranil; Bischoff, Markus; Rohde, Manfred; Josten, Michaele; Sahl, Hans-Georg; Herrmann, Mathias; Müller, Rolf

    2016-01-01

    Purpose The emergence of bacteria that are resistant to many currently used drugs emphasizes the need to discover and develop new antibiotics that are effective against such multi-resistant strains. Kendomycin is a novel polyketide that has a unique quinone methide ansa structure and various biological properties. This compound exhibits strong antibacterial activity against Gram-negative and Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Despite the promise of kendomycinin in several therapeutic areas, its mode of action has yet to be identified. Methods In this study, we used a multidisciplinary approach to gain insight into the antibacterial mechanism of this compound. Results The antibacterial activity of kendomycin appears to be bacteriostatic rather than bactericidal. Kendomycin inhibited the growth of the MRSA strain COL at a low concentration (MIC of 5 μg/mL). Proteomic analysis and gene transcription profiling of kendomycin-treated cells indicated that this compound affected the regulation of numerous proteins and genes involved in central metabolic pathways, such as the tricarboxylic acid (TCA) cycle (SdhA) and gluconeogenesis (PckA and GapB), cell wall biosynthesis and cell division (FtsA, FtsZ, and MurAA), capsule production (Cap5A and Cap5C), bacterial programmed cell death (LrgA and CidA), the cellular stress response (ClpB, ClpC, ClpP, GroEL, DnaK, and GrpE), and oxidative stress (AhpC and KatA). Electron microscopy revealed that kendomycin strongly affected septum formation during cell division. Most kendomycin-treated cells displayed incomplete septa with abnormal morphology. Conclusions Kendomycin might directly or indirectly affect the cell division machinery, protein stability, and programmed cell death in S. aureus. Additional studies are still needed to obtain deeper insight into the mode of action of kendomycin. PMID:26795276

  13. A class of selective antibacterials derived from a protein kinase inhibitor pharmacophore

    SciTech Connect

    Miller, J. Richard; Dunham, Steve; Mochalkin, Igor; Banotai, Craig; Bowman, Matthew; Buist, Susan; Dunkle, Bill; Hanna, Debra; Harwood, H. James; Huband, Michael D.; Karnovsky, Alla; Kuhn, Michael; Limberakis, Chris; Liu, Jia Y.; Mehrens, Shawn; Mueller, W. Thomas; Narasimhan, Lakshmi; Ogden, Adam; Ohren, Jeff; Prasad, J.V.N. Vara; Shelly, John A.; Skerlos, Laura; Sulavik, Mark; Thomas, V. Hayden; VanderRoest, Steve; Wang, LiAnn; Wang, Zhigang; Whitton, Amy; Zhu, Tong; Stover, C. Kendall

    2009-06-25

    As the need for novel antibiotic classes to combat bacterial drug resistance increases, the paucity of leads resulting from target-based antibacterial screening of pharmaceutical compound libraries is of major concern. One explanation for this lack of success is that antibacterial screening efforts have not leveraged the eukaryotic bias resulting from more extensive chemistry efforts targeting eukaryotic gene families such as G protein-coupled receptors and protein kinases. Consistent with a focus on antibacterial target space resembling these eukaryotic targets, we used whole-cell screening to identify a series of antibacterial pyridopyrimidines derived from a protein kinase inhibitor pharmacophore. In bacteria, the pyridopyrimidines target the ATP-binding site of biotin carboxylase (BC), which catalyzes the first enzymatic step of fatty acid biosynthesis. These inhibitors are effective in vitro and in vivo against fastidious Gram-negative pathogens including Haemophilus influenzae. Although the BC active site has architectural similarity to those of eukaryotic protein kinases, inhibitor binding to the BC ATP-binding site is distinct from the protein kinase-binding mode, such that the inhibitors are selective for bacterial BC. In summary, we have discovered a promising class of potent antibacterials with a previously undescribed mechanism of action. In consideration of the eukaryotic bias of pharmaceutical libraries, our findings also suggest that pursuit of a novel inhibitor leads for antibacterial targets with active-site structural similarity to known human targets will likely be more fruitful than the traditional focus on unique bacterial target space, particularly when structure-based and computational methodologies are applied to ensure bacterial selectivity.

  14. A class of selective antibacterials derived from a protein kinase inhibitor pharmacophore.

    PubMed

    Miller, J Richard; Dunham, Steve; Mochalkin, Igor; Banotai, Craig; Bowman, Matthew; Buist, Susan; Dunkle, Bill; Hanna, Debra; Harwood, H James; Huband, Michael D; Karnovsky, Alla; Kuhn, Michael; Limberakis, Chris; Liu, Jia Y; Mehrens, Shawn; Mueller, W Thomas; Narasimhan, Lakshmi; Ogden, Adam; Ohren, Jeff; Prasad, J V N Vara; Shelly, John A; Skerlos, Laura; Sulavik, Mark; Thomas, V Hayden; VanderRoest, Steve; Wang, LiAnn; Wang, Zhigang; Whitton, Amy; Zhu, Tong; Stover, C Kendall

    2009-02-10

    As the need for novel antibiotic classes to combat bacterial drug resistance increases, the paucity of leads resulting from target-based antibacterial screening of pharmaceutical compound libraries is of major concern. One explanation for this lack of success is that antibacterial screening efforts have not leveraged the eukaryotic bias resulting from more extensive chemistry efforts targeting eukaryotic gene families such as G protein-coupled receptors and protein kinases. Consistent with a focus on antibacterial target space resembling these eukaryotic targets, we used whole-cell screening to identify a series of antibacterial pyridopyrimidines derived from a protein kinase inhibitor pharmacophore. In bacteria, the pyridopyrimidines target the ATP-binding site of biotin carboxylase (BC), which catalyzes the first enzymatic step of fatty acid biosynthesis. These inhibitors are effective in vitro and in vivo against fastidious gram-negative pathogens including Haemophilus influenzae. Although the BC active site has architectural similarity to those of eukaryotic protein kinases, inhibitor binding to the BC ATP-binding site is distinct from the protein kinase-binding mode, such that the inhibitors are selective for bacterial BC. In summary, we have discovered a promising class of potent antibacterials with a previously undescribed mechanism of action. In consideration of the eukaryotic bias of pharmaceutical libraries, our findings also suggest that pursuit of a novel inhibitor leads for antibacterial targets with active-site structural similarity to known human targets will likely be more fruitful than the traditional focus on unique bacterial target space, particularly when structure-based and computational methodologies are applied to ensure bacterial selectivity. PMID:19164768

  15. ANTIBACTERIAL PROPERTIES AND DRYING EFFECTS OF FLAX DENIM AND ANTIBACTERIAL PROPERTIES OF NONWOVEN FLAX FABRIC

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A modification of "AATCC Test Method 100-1999, Antibacterial Finishes on Textile Materials: Assessment of," was used for assaying the antibacterial properties of denim containing various flax levels. When the effect of drying was looked at, increased flax content did not improve the rate of drying ...

  16. Superhydrophobic PVDF and PVDF-HFP nanofibrous mats with antibacterial and anti-biofouling properties

    NASA Astrophysics Data System (ADS)

    Spasova, M.; Manolova, N.; Markova, N.; Rashkov, I.

    2016-02-01

    Superhydrophobic nanofibrous materials of poly(vinylidene fluoride) (PVDF) and poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) were prepared by one-pot electrospinning technique. The mats were decorated with ZnO nanoparticles with silanized surface and a model drug - 5-chloro-8-hydroxyquinolinol (5Cl8HQ). The obtained hybrid nanofibrous materials were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), contact angle measurements, mechanical and microbiological tests. The results showed that the incorporation of ZnO nanoparticles into PVDF and PVDF-HFP nanofibers increased the hydrophobicity (contact angle 152°), improved the thermal stability and imparted to the nanofibrous materials anti-adhesive and antimicrobial properties. The mats containing the model drug possessed antibacterial activity against Escherichia coli and Staphylococcus aureus. The results suggested that the obtained hybrid mats could find potential biomedical applications requiring antibacterial and anti-biofouling properties.

  17. Synthesis and antibacterial and antifungal evaluation of some chalcone based sulfones and bisulfones.

    PubMed

    Konduru, Naveen Kumar; Dey, Sunita; Sajid, Mohammad; Owais, Mohammad; Ahmed, Naseem

    2013-01-01

    Two series of chalcone based sulfone and bisulfone derivatives were synthesized using chalcone, thiophenol and sodium metal at room temperature, followed by oxidation of chalcone sulfides with m-CPBA at 0 °C in a novel method. Both sulfones and bisulfones were evaluated for their antimicrobial activities against Aspergillus niger and Candida albicans (yeast), Bacillus subtilis and Staphylococcus aureus (Gram (+) bacteria) and Pseudomonas aeruginosa and Salmonella typhimurium (Gram (-) bacteria) strains. Among them, compounds 2c, 3c, 6c, 7c, 8c and 9c have shown high antifungal activity against C. albicans compare to reference drugs viz. Amphotericin-B and Nystatin. Compound 1c has shown slightly better antibacterial activity against B. subtilis and compounds 5c, 6c and 7c have shown excellent antibacterial activity against S. typhimurium in compare to reference drugs Ampicillin and Kanamycin. PMID:23202847

  18. Short cationic lipopeptides as effective antibacterial agents: Design, physicochemical properties and biological evaluation.

    PubMed

    Azmi, Fazren; Elliott, Alysha G; Marasini, Nirmal; Ramu, Soumya; Ziora, Zyta; Kavanagh, Angela M; Blaskovich, Mark A T; Cooper, Matthew A; Skwarczynski, Mariusz; Toth, Istvan

    2016-05-15

    The spread of drug-resistant bacteria has imparted a sense of urgency in the search for new antibiotics. In an effort to develop a new generation of antibacterial agents, we have designed de novo charged lipopeptides inspired by natural antimicrobial peptides. These short lipopeptides are composed of cationic lysine and hydrophobic lipoamino acids that replicate the amphiphilic properties of natural antimicrobial peptides. The resultant lipopeptides were found to self-assemble into nanoparticles. Some were effective against a variety of Gram-positive bacteria, including strains resistant to methicillin, daptomycin and/or vancomycin. The lipopeptides were not toxic to human kidney and liver cell lines and were highly resistant to tryptic degradation. Transmission electron microscopy analysis of bacteria cells treated with lipopeptide showed membrane-damage and lysis with extrusion of cytosolic contents. With such properties in mind, these lipopeptides have the potential to be developed as new antibacterial agents against drug-resistant Gram-positive bacteria. PMID:27048775

  19. Drug disposition in cystic fibrosis.

    PubMed

    Rey, E; Tréluyer, J M; Pons, G

    1998-10-01

    There are many pathological changes in patients with cystic fibrosis (CF) which can lead to alterations in drug disposition. Although, in patients with CF, the extent of drug absorption varies widely and the rate of absorption is slower, bioavailability is not altered. Plasma protein binding for the majority of drugs studied did not differ in patients with CF compared with control groups. The difference in volume of distribution of most drugs between patients with CF and healthy individuals vanished when corrected for lean body mass. Despite hepatic dysfunction, patients with CF have enhanced clearance of many, but not all, drugs. Phase I mixed-function oxidases are selectively affected: cytochrome P450 (CYP) 1A2 and CYP2C8 have enhanced activity, while other CYP isoforms such as CYP2C9 and CYP3A4 are unaffected. Increased phase II activities are also demonstrated: glucuronyl transferase, acetyl transferase (NAT1) and sulfotransferase. The increased hepatic clearance of drugs in the presence of CF may be the consequence of disease-specific changes in both enzyme activity and/or drug transport within the liver. The renal clearance (CLR) of many drugs in patients with CF is enhanced although there has been no pathological abnormality identified which could explain this finding: glomerular filtration rate and tubular secretion appear normal in patients with CF. The precise mechanisms for enhanced drug clearance in patients with CF remain to be elucidated. The optimisation of antibiotic therapy in patients with CF includes increasing the dose of beta-lactams by 20 to 30% and monitoring plasma concentrations of aminoglycosides. The appropriate dosage of quinolones has not been definitively established. PMID:9812180

  20. Antibacterial activity of cefquinome against equine bacterial pathogens.

    PubMed

    Thomas, E; Thomas, V; Wilhelm, C

    2006-06-15

    Cefquinome is known for its use as an antibacterial drug in cattle and pigs. The objective of this study was to evaluate the antibacterial activity of cefquinome against equine pathogenic bacteria. The minimum inhibitory concentration (MIC) of cefquinome was determined for a total of 205 strains, which had recently been isolated in Europe from diseased horses (respiratory infection, foal septicaemia). The bactericidal activity was tested against 19 strains using the time killing method. The post-antibiotic effect (PAE) and post-antibiotic sub-MIC effect (PA SME) were determined against 12 strains. Cefquinome showed high activity against Actinobacillus equuli and streptococci (MIC(90) of 0.016 and 0.032microg/mL), Enterobacteriaceae (MIC(90)=0.125microg/mL) and staphylococci (MIC(90)=0.5microg/mL). The activity was limited against Rhodococcus spp. and Pseudomonas spp. Cefquinome was shown to be a time dependent bactericidal antibiotic against the target pathogens, killing occurring at a concentration close to the MIC. A PAE of 0.5-10h was calculated against streptococci whereas no PAE was observed for Escherichia coli. A longer PA SME was determined for streptococci (3.3 to >24h with a killing effect) and E. coli (0.5-13.9h). Cefquinome was shown to have a broad spectrum of activity which covers many equine pathogens. PMID:16455213

  1. Nanotechnology Formulations for Antibacterial Free Fatty Acids and Monoglycerides.

    PubMed

    Jackman, Joshua A; Yoon, Bo Kyeong; Li, Danlin; Cho, Nam-Joon

    2016-01-01

    Free fatty acids and monoglycerides have long been known to possess broad-spectrum antibacterial activity that is based on lytic behavior against bacterial cell membranes. Considering the growing challenges of drug-resistant bacteria and the need for new classes of antibiotics, the wide prevalence, affordable cost, and broad spectrum of fatty acids and monoglycerides make them attractive agents to develop for healthcare and biotechnology applications. The aim of this review is to provide a brief introduction to the history of antimicrobial lipids and their current status and challenges, and to present a detailed discussion of ongoing research efforts to develop nanotechnology formulations of fatty acids and monoglycerides that enable superior in vitro and in vivo performance. Examples of nano-emulsions, liposomes, solid lipid nanoparticles, and controlled release hydrogels are presented in order to highlight the potential that lies ahead for fatty acids and monoglycerides as next-generation antibacterial solutions. Possible application routes and future directions in research and development are also discussed. PMID:26950108

  2. Adsorption of quinolone antibiotics in spherical mesoporous silica: Effects of the retained template and its alkyl chain length.

    PubMed

    Liang, Zhijie; Zhaob, Zhiwei; Sun, Tianyi; Shi, Wenxin; Cui, Fuyi

    2016-03-15

    In this study, mesoporous silica (meso-silica) MCM-41 and those with the templates retained were synthesized and characterized. Adsorption capacities of the synthesized materials towards typical quinolone antibiotic pollutants, enrofloxacin and norfloxacin as representative, were investigated, and effects of the alkyl chain length of the templates on the adsorption capacity were evaluated. The results of this study indicated that the retained templates enhanced the adsorption capacities (Qmax) of the meso-silica MCM-41 toward hydrophobic enrofloxacin, but had an inhibitory effect on that towards hydrophilic norfloxacin, which were attributed to the hydrophobic inter-environment created by the long alkyl chains of the retained templates. Importantly, the adsorption capacity increased with the increase of the alkyl chain length of the retained templates. PMID:26642441

  3. Simultaneous determination of multiple (fluoro)quinolone antibiotics in food samples by a one-step fluorescence polarization immunoassay.

    PubMed

    Mi, Tiejun; Wang, Zhanhui; Eremin, Sergei A; Shen, Jianzhong; Zhang, Suxia

    2013-10-01

    This paper describes a rapid one-step fluorescence polarization immunoassay (FPIA) for the simultaneous determination of multiple (fluoro)quinolone antibiotics (FQs) in food samples. Several fluorescent tracers were synthesized and evaluated in the FPIA method based on a broad-specificity of monoclonal antibodies toward FQs. The heterogeneous tracer, SAR-5-FAM, was considered as the optimal choice to prepare the immunocomplex single reagent, which allows a rapid and sensitive displacement reaction by addition of analytes. Optimized single-reagent FPIA exhibited broad cross-reactivities in the range of 7.8-172.2% with 16 FQs tested and was capable of determining most FQs at the level of maximum residue limits. Recoveries for spiked milk and chicken muscle samples were from 77.8 to 116%, with relative standard deviation lower than 17.4%. Therefore, this method could be applicable in routine screening analysis of multiple FQ residues in food samples. PMID:24050679

  4. Structure of the Dioxygenase AsqJ: Mechanistic Insights into a One-Pot Multistep Quinolone Antibiotic Biosynthesis.

    PubMed

    Bräuer, Alois; Beck, Philipp; Hintermann, Lukas; Groll, Michael

    2016-01-01

    Multienzymatic cascades are responsible for the biosynthesis of natural products and represent a source of inspiration for synthetic chemists. The Fe(II)/α-ketoglutarate-dependent dioxygenase AsqJ from Aspergillus nidulans is outstanding because it stereoselectively catalyzes both a ferryl-induced desaturation reaction and epoxidation on a benzodiazepinedione. Interestingly, the enzymatically formed spiro epoxide spring-loads the 6,7-bicyclic skeleton for non-enzymatic rearrangement into the 6,6-bicyclic scaffold of the quinolone alkaloid 4'-methoxyviridicatin. Herein, we report different crystal structures of the protein in the absence and presence of synthesized substrates, surrogates, and intermediates that mimic the various stages of the reaction cycle of this exceptional dioxygenase. PMID:26553478

  5. An integrated microfluidic system for diagnosis of the resistance of Helicobacter pylori to quinolone-based antibiotics.

    PubMed

    Chao, Chih-Yu; Wang, Chih-Hung; Che, Yu-Jui; Kao, Cheng-Yen; Wu, Jiunn-Jong; Lee, Gwo-Bin

    2016-04-15

    Helicobacter pylori (H. pylori) is a species of bacteria that can colonize the human stomach mucosa. It is closely associated with gastric diseases such as ulcer and inflammation. Recently, some H. pylori strains were found to express resistance to a family of antibiotics known as quinolones due to single-point mutations. Although traditional polymerase chain reaction (PCR) and molecular diagnostic-based approaches can be used to determine the presence and abundance of antibiotic-resistant H. pylori strains, such processes are relatively expensive, labor-intensive, and require bulky and costly equipment. This study therefore reports an advanced diagnostic assay performed on an integrated microfluidic system for rapid detection of antibiotic resistance in H. pylori. The assay features three components: (1) nucleic acid extraction by specific probe-conjugated magnetic beads, (2) amplification of the target deoxyribonucleic acid (DNA) fragments by using single-nucleotide-polymorphism polymerase chain reaction (SNP-PCR), and (3) optical detection of the PCR products. The device integrates several microfluidic components including micro-pumps, normally-closed micro-valves, and reaction chambers such that the entire diagnostic assay can be automatically executed on a single microfluidic system within one hour with detection limits of 10(0), 10(2), and 10(2) bacterial cells for H. pylori detection and two different SNP sites strains. Three PCR-based assays for determining presence of H. pylori infection and two DNA single-point mutation assays aimed at determining whether the infected strains were resistant to quinolone can be performed simultaneously on a single chip, suggesting that this microfluidic system could be a promising tool for rapid diagnosis of the presence of antibiotic-resistant H. pylori strains. PMID:26630283

  6. Prevalence of Quinolone Resistance Genes Among Extended-Spectrum B-Lactamase-Producing Escherichia coli in Mashhad, Iran

    PubMed Central

    Harifi Mood, Elnaz; Meshkat, Zahra; Izadi, Nafiseh; Rezaei, Maryam; Amel Jamehdar, Saeid; Naderi Nasab, Mahboubeh

    2015-01-01

    Background: Escherichia coli is an important bacterial species based on incidence and associated infection severity. Some E. coli strains produce extended-spectrum beta lactamase (ESBL) and are called ESBL-producing E. coli. These strains are resistant to most classes of cephalosporin and a number of other classes of antibiotics. Plasmids carrying qnr genes have been found to transmit quinolone resistance. Objectives: The aim of this study was to determine the frequency of qnr genes in ESBL-producing and non-ESBL-producing E. coli isolated from outpatient and hospitalized patient clinical specimens from Imam Reza hospital in Mashhad, Iran. Materials and Methods: Two hundred E. coli strains, isolated from different clinical specimens were used. ESBL-producing E. coli were detected by determining susceptibility to ceftazidime, cefotaxime, and cefpodoxime with the phenotypic confirmatory test (PCT). PCR analysis was employed to detect the qnrA, qnrB, qnrS, blaTEM, and blaSHV genes. Results: Eighty-six (43%) isolates were ciprofloxacin-resistant. The PCT identified 85 (42.5%) of 200 E. coli isolates as ESBL-producing. The blaTEM, blaSHV, qnrA, qnrB, and qnrS gene were found in 65 (76.47%), 23 (27%), 63 (31%), 34 (17%), and 14 (7%) isolates, respectively. Conclusions: The high prevalence of quinolone resistance genes, which indicates antibiotic resistance, in the Imam Reza Hospital of Mashhad is a major concern. Hence, the antibiotics prescription policy should be revised, and infection control measures should be improved. PMID:26870307

  7. Multidrug Resistance in Quinolone-Resistant Gram-Negative Bacteria Isolated from Hospital Effluent and the Municipal Wastewater Treatment Plant.

    PubMed

    Vaz-Moreira, Ivone; Varela, Ana Rita; Pereira, Thamiris V; Fochat, Romário C; Manaia, Célia M

    2016-03-01

    This study is aimed to assess if hospital effluents represent an important supplier of multidrug-resistant (MDR) Gram-negative bacteria that, being discharged in the municipal collector, may be disseminated in the environment and bypassed in water quality control systems. From a set of 101 non-Escherichia coli Gram-negative bacteria with reduced susceptibility to quinolones, was selected a group of isolates comprised by those with the highest indices of MDR (defined as nonsusceptibility to at least one agent in six or more antimicrobial categories, MDR ≥6) or resistance to meropenem or ceftazidime (n = 25). The isolates were identified and characterized for antibiotic resistance phenotype, plasmid-mediated quinolone resistance (PMQR) genes, and other genetic elements and conjugative capacity. The isolates with highest MDR indices were mainly from hospital effluent and comprised ubiquitous bacterial groups of the class Gammaproteobacteria, of the genera Aeromonas, Acinetobacter, Citrobacter, Enterobacter, Klebsiella, and Pseudomonas, and of the class Flavobacteriia, of the genera Chryseobacterium and Myroides. In this group of 25 strains, 19 identified as Gammaproteobacteria harbored at least one PMQR gene (aac(6')-Ib-cr, qnrB, qnrS, or oqxAB) or a class 1 integron gene cassette encoding aminoglycoside, sulfonamide, or carbapenem resistance. Most of the E. coli J53 transconjugants with acquired antibiotic resistance resulted from conjugation with Enterobacteriaceae. These transconjugants demonstrated acquired resistance to a maximum of five classes of antibiotics, one or more PMQR genes and/or a class 1 integron gene cassette. This study shows that ubiquitous bacteria, other than those monitored in water quality controls, are important vectors of antibiotic resistance and can be disseminated from hospital effluent to aquatic environments. This information is relevant to support management options aiming at the control of this public health problem. PMID:26469134

  8. Quinolone resistant Aeromonas spp. as carriers and potential tracers of acquired antibiotic resistance in hospital and municipal wastewater.

    PubMed

    Varela, Ana Rita; Nunes, Olga C; Manaia, Célia M

    2016-01-15

    Members of the genus Aeromonas are recognized carriers of antibiotic resistance in aquatic environments. However, their importance on the spread of resistance from hospital effluents to the environment is poorly understood. Quinolone resistant Aeromonas spp. (n = 112) isolated from hospital effluent (HE) and from raw (RWW) and treated wastewater (TWW) of the receiving urban wastewater treatment plant (UWTP) were characterized. Species identification and genetic intraspecies diversity were assessed based on the 16S rRNA, cpn60 and gyrB genes sequence analysis. The antibiotic resistance phenotypes and genotypes (qnrA, qnrB, qnrC, qnrD, qnrS, qnrVC; qepA; oqxAB; aac(6′)-Ib-cr; blaOXA; incU) were analyzed in function of the origin and taxonomic group. Most isolates belonged to the species Aeromonas caviae and Aeromonas hydrophila (50% and 41%, respectively). The quinolone and the beta-lactamase resistance genes aac(6′)-Ib-cr and blaOXA, including gene blaOXA-101, identified for the first time in Aeromonas spp., were detected in 58% and 56% of the isolates, respectively, with identical prevalence in HE and UWTP wastewater. In contrast, the gene qnrS2 was observed mainly in isolates from the UWTP (51%) and rarely in HE isolates (3%), suggesting that its origin is not the clinical setting. Bacterial groups and genes that allow the identification of major routes of antibiotic resistance dissemination are valuable tools to control this problem. In this study, it was concluded that members of the genus Aeromonas harboring the genes aac(6′)-Ib-cr and blaOXA are relevant tracers of antibiotic resistance dissemination in wastewater habitats, while those yielding the gene qnrS2 allow the traceability from non-clinical sources. PMID:26546762

  9. In Vitro Antibacterial Activities of JNJ-Q2, a New Broad-Spectrum Fluoroquinolone ▿ ‡

    PubMed Central

    Morrow, Brian J.; He, Wenping; Amsler, Karen M.; Foleno, Barbara D.; Macielag, Mark J.; Lynch, A. Simon; Bush, Karen

    2010-01-01

    JNJ-Q2, a novel fluorinated 4-quinolone, was evaluated for its antibacterial potency by broth and agar microdilution MIC methods in studies focused on skin and respiratory tract pathogens, including strains exhibiting contemporary fluoroquinolone resistance phenotypes. Against a set of 118 recent clinical isolates of Streptococcus pneumoniae, including fluoroquinolone-resistant variants bearing multiple DNA topoisomerase target mutations, an MIC90 value for JNJ-Q2 of 0.12 μg/ml was determined, indicating that it was 32-fold more potent than moxifloxacin. Against a collection of 345 recently collected methicillin-resistant Staphylococcus aureus (MRSA) isolates, including 256 ciprofloxacin-resistant strains, the JNJ-Q2 MIC90 value was 0.25 μg/ml, similarly indicating that it was 32-fold more potent than moxifloxacin. The activities of JNJ-Q2 against Gram-negative pathogens were generally comparable to those of moxifloxacin. In further studies, JNJ-Q2 exhibited bactericidal activities at 2× and 4× MIC levels against clinical isolates of S. pneumoniae and MRSA with various fluoroquinolone susceptibilities, and its activities were enhanced over those of moxifloxacin. In these studies, the activity exhibited against strains bearing gyrA, parC, or gyrA plus parC mutations was indicative of the relatively balanced (equipotent) activity of JNJ-Q2 against the DNA topoisomerase target enzymes. Finally, determination of the relative rates or frequencies of the spontaneous development of resistance to JNJ-Q2 at 2× and 4× MICs in S. pneumoniae, MRSA, and Escherichia coli were indicative of a lower potential for resistance development than that for current fluoroquinolones. In conclusion, JNJ-Q2 exhibits a range of antibacterial activities in vitro that is supportive of its further evaluation as a potential new agent for the treatment of skin and respiratory tract infections. PMID:20176911

  10. A general ANN-based multitasking model for the discovery of potent and safer antibacterial agents.

    PubMed

    Speck-Planche, A; Cordeiro, M N D S

    2015-01-01

    Bacteria have been one of the world's most dangerous and deadliest pathogens for mankind, nowadays giving rise to significant public health concerns. Given the prevalence of these microbial pathogens and their increasing resistance to existing antibiotics, there is a pressing need for new antibacterial drugs. However, development of a successful drug is a complex, costly, and time-consuming process. Quantitative Structure-Activity Relationships (QSAR)-based approaches are valuable tools for shortening the time of lead compound identification but also for focusing and limiting time-costly synthetic activities and in vitro/vivo evaluations. QSAR-based approaches, supported by powerful statistical techniques such as artificial neural networks (ANNs), have evolved to the point of integrating dissimilar types of chemical and biological data. This chapter reports an overview of the current research and potential applications of QSAR modeling tools toward the rational design of more efficient antibacterial agents. Particular emphasis is given to the setup of multitasking models along with ANNs aimed at jointly predicting different antibacterial activities and safety profiles of drugs/chemicals under diverse experimental conditions. PMID:25502375

  11. PEGylated ofloxacin nanoparticles render strong antibacterial activity against many clinically important human pathogens.

    PubMed

    Marslin, Gregory; Revina, Ann Mary; Khandelwal, Vinoth Kumar Megraj; Balakumar, Krishnamoorthy; Sheeba, Caroline J; Franklin, Gregory

    2015-08-01

    The rise of bacterial resistance against important drugs threatens their clinical utility. Fluoroquinones, one of the most important classes of contemporary antibiotics has also reported to suffer bacterial resistance. Since the general mechanism of bacterial resistance against fluoroquinone antibiotics (e.g. ofloxacin) consists of target mutations resulting in reduced membrane permeability and increased efflux by the bacteria, strategies that could increase bacterial uptake and reduce efflux of the drug would provide effective treatment. In the present study, we have compared the efficiencies of ofloxacin delivered in the form of free drug (OFX) and as nanoparticles on bacterial uptake and antibacterial activity. Although both poly(lactic-co-glycolic acid) (OFX-PLGA) and methoxy poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (OFX-mPEG-PLGA) nanoformulations presented improved bacterial uptake and antibacterial activity against all the tested human bacterial pathogens, namely, Escherichia coli, Proteus vulgaris, Salmonella typhimurium, Pseudomonas aeruginosa, Klebsiella pneumoniae and Staphylococcus aureus, OFX-mPEG-PLGA showed significantly higher bacterial uptake and antibacterial activity compared to OFX-PLGA. We have also found that mPEG-PLGA nanoencapsulation could significantly inhibit Bacillus subtilis resistance development against OFX. PMID:26005932

  12. Antibacterial Effects of Cissus welwitschii and Triumfetta welwitschii Extracts against Escherichia coli and Bacillus cereus

    PubMed Central

    2015-01-01

    Antibiotic resistance has increased sharply, while the pace for the development of new antimicrobials has slowed down. Plants provide an alternative source for new drugs. This study aimed to screen extracts from Cissus welwitschii and Triumfetta welwitschii for antibacterial activity against Escherichia coli and Bacillus cereus. The tests conducted included a susceptibility determination test, analysis of the effect of T. welwitschii on cell wall integrity, and transport across the membrane. It was found that the T. welwitschii methanol extracts were more effective than the water extracts and had the lowest minimum inhibitory concentration and minimum bactericidal concentration at 0.125 mg/mL and 0.5 mg/mL, respectively, against E. coli and B. cereus. The C. welwitschii extract caused the most drug accumulation in E. coli. In B. cereus, no significant drug accumulation was observed. Nucleic acid leakage in B. cereus and E. coli and protein leakage in E. coli were observed after exposure to the T. welwitschii extract. The extracts from T. welwitschii had greater antibacterial activity than the extracts from C. welwitschii. T. welwitschii may be a potential source of lead compounds for that could be developed into antibacterial agents. PMID:26904744

  13. Antibacterial activities of nemonoxacin against clinical isolates of Staphylococcus aureus: an in vitro comparison with three fluoroquinolones.

    PubMed

    Li, Zhaoxia; Liu, Youning; Wang, Rui; Li, Aimin

    2014-11-01

    In comparison with ciprofloxacin, levofloxacin and moxifloxacin, antimicrobial activity of nemonoxacin against ciprofloxacin-susceptible/-resistant methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) was determined with the availability to select resistant mutants evaluated. Minimum inhibitory concentrations and mutant prevention concentrations of quinolones were determined by agar dilution method, that concentrated bacterial cells were spread onto Mueller-Hinton agar plates containing antibacterials at different concentrations. Selection index (SI) was calculated. Minimum inhibitory concentration and mutant prevention concentration of nemonoxacin were 0.063 and 0.25 ?g/mL for ciprofloxacin-susceptible MSSA and those were 0.5 and 4.0 ?g/mL for ciprofloxacin-resistant MSSA, lower than observations of three fluoroquinolones distinctly. SI of nemonoxacin and moxifloxacin were similar, with narrower mutant selective window than levofloxacin and ciprofloxacin. Minimum inhibitory concentration and mutant prevention concentration of nemonoxacin were 0.25 and 2.0 ?g/mL for ciprofloxacin-susceptible MRSA, which were 0.5 and 16.0 ?g/mL for ciprofloxacin-resistant MRSA. Values were lower than those determined from fluoroquinolones. Nemonoxacin presents good antimicrobial activity against clinical isolates of S. aureus, especially for ciprofloxacin-resistant strains. But stepwise mutant accumulation of ciprofloxacin-resistant MRSA can be hardly inhibited by nemonoxacin with pharmacokinetic parameters considered. PMID:25129332

  14. Synthesis and antibacterial activity of littorachalcone and related diphenyl ethers.

    PubMed

    Kraus, George A; Kumar, Ganesh; Phillips, Gregory; Michalson, Kris; Mangano, Maria

    2008-04-01

    Littorachalcone (1) and diacid 10 were synthesized by direct routes. The antibacterial activity of 1, 10 and synthetic precursors were evaluated. Dialdehyde 3a showed potent antibacterial activity. PMID:18343663

  15. Synthesis and antibacterial activity of monocyclic 3-carboxamide tetramic acids

    PubMed Central

    Jeong, Yong-Chul

    2013-01-01

    Summary A chemical library of carboxamide-substituted tetramates designed by analogy with antibacterial natural products, a method for their rapid construction, and the evaluation of their antibacterial activity is reported. PMID:24204399

  16. Antibacterial and Antiviral Responses of Larval Heliothis virescens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In order to better understand the immune response of Heliothis virescens against microbial entomopathogens several orthologs of antibacterial response proteins were identified and extracted from Heliobase (an EST database for H. virescens) for detailed study. Induction of these antibacterial prote...

  17. A novel antibacterial resin composite for improved dental restoratives.

    PubMed

    Weng, Yiming; Howard, Leah; Guo, Xia; Chong, Voon Joe; Gregory, Richard L; Xie, Dong

    2012-06-01

    A novel furanone-containing antibacterial resin composite has been prepared and evaluated. compressive strength (CS) and Streptococcus mutans viability were used to evaluate the mechanical strength and antibacterial activity of the composites. The modified resin composites showed a significant antibacterial activity without substantially decreasing the mechanical strengths. With 5-30 % addition of the furanone derivative, the composite kept its original CS unchanged but showed a significant antibacterial activity with a 16-68 % reduction in the S. mutans viability. Further, the antibacterial function of the new composite was not affected by human saliva. The aging study indicates that the composite may have a long-lasting antibacterial function. Within the limitations of this study, it appears that the experimental antibacterial resin composite may potentially be developed into a clinically attractive dental restorative due to its high mechanical strength and antibacterial function. PMID:22466818

  18. Drug forecast – the peptide deformylase inhibitors as antibacterial agents

    PubMed Central

    Guay, David R P

    2007-01-01

    The relatively rapid development of microbial resistance after the entry of every new antimicrobial into the marketplace necessitates a constant supply of new agents to maintain effective pharmacotherapy. Despite extensive efforts to identify novel lead compounds from molecular targets, only the peptide deformylase inhibitors (PDIs) have shown any real promise, with some advancing to phase I human trials. Bacterial peptide deformylase, which catalyzes the removal of the N-formyl group from N-terminal methionine following translation, is essential for bacterial protein synthesis, growth, and survival. The majority of PDIs are pseudopeptide hydroxamic acids and two of these (IV BB-83698 and oral NVP LBM-415) entered phase I human trials. However, agents to the present have suffered from major potential liabilities. Their in vitro activity has been limited to gram-positive aerobes and some anaerobes and has been quite modest against the majority of such species (MIC90 values ranging from 1–8 mg/L). They have exerted bacteriostatic, not bacteriocidal, activity, thus reducing their potential usefulness in the management of serious infections in the immunocompromised. The relative ease with which microorganisms have been able to develop resistance and the multiple available mechanisms of resistance (mutations in fmt, defB, folD genes; AcrAB/TolC efflux pump; overexpression of peptide deformylase) are worrisome. These could portend a short timespan of efficacy after marketing. Despite these current liabilities, further pursuit of more potent and broader spectrum PDIs which are less susceptible to bacterial mechanisms of resistance is still warranted. PMID:18472972

  19. Antibacterial Drug Leads: DNA and Enzyme Multi-Targeting

    PubMed Central

    Zhu, Wei; Wang, Yang; Li, Kai; Gao, Jian; Huang, Chun-Hsiang; Chen, Chun-Chi; Ko, Tzu-Ping; Zhang, Yonghui; Guo, Rey-Ting; Oldfield, Eric

    2015-01-01

    We report the results of an investigation of the activity of a series of amidine and bisamidine compounds against Staphylococcus aureus and Escherichia coli. The most active compounds bound to an AT-rich DNA dodecamer (CGCGAATTCGCG)2, and using DSC were found to increase the melting transition by up to 24 °C. Several compounds also inhibited undecaprenyl diphosphate synthase (UPPS) with IC50 values of 100–500 nM and we found good correlations (R2 = 0.89, S. aureus; R2 = 0.79, E. coli)) between experimental and predicted cell growth inhibition by using DNA ΔTm and UPPS IC50 experimental results together with 1 computed descriptor. We also solved the structures of three bisamidines binding to DNA as well as three UPPS structures. Overall, the results are of general interest in the context of the development of resistance-resistant antibiotics that involve multi-targeting. PMID:25574764

  20. Molecular epidemiological survey of the quinolone- and carbapenem-resistant genotype and its association with the type III secretion system in Pseudomonas aeruginosa.

    PubMed

    Ferreira, Melina Lorraine; Dantas, Raquel Cavalcanti; Faria, Ana Luiza Souza; Gonçalves, Iara Rossi; Silveira de Brito, Cristiane; Queiroz, Lícia Ludendorff; Gontijo-Filho, Paulo P; Ribas, Rosineide Marques

    2015-03-01

    This study evaluated the predictors of mortality and the impact of inappropriate therapy on the outcomes of patients with bacteraemia and ventilator-associated pneumonia (VAP). Additionally, we evaluated the correlation of the type III secretion system (TTSS) effector genotype with resistance to carbapenems and fluoroquinolones, mutations in the quinolone resistance-determining regions (QRDRs), metallo-β-lactamase and virulence factors. A retrospective cohort was conducted at a tertiary hospital in patients with multidrug-resistant (MDR) P. aeruginosa bacteraemia (157 patients) and VAP (60 patients). The genes for blaIMP, blaVIM, blaSIM, blaGIM and blaSPM and virulence genes (exoT, exoS, exoY, exoU, lasB, algD and toxA) were detected; sequencing was conducted for QRDR genes on fluoroquinolone-resistant strains. The multivariate analyses showed that the predictors independently associated with death in patients with bacteraemia were cancer and inappropriate therapy. Carbapenem resistance was more frequent among strains causing VAP (53.3 %), and in blood we observed the blaSPM genotype (66.6 %) and blaVIM genotype (33.3 %). The exoS gene was found in all isolates, whilst the frequency was low for exoU (9.4 %). Substitution of threonine to isoleucine at position 83 in gyrA was the most frequent mutation among fluoroquinolone-resistant strains. Our study showed a mutation at position 91 in the parC gene (Glu91Lys) associated with a mutation in gyrA (Thre83Ile) in a strain of extensively drug-resistant P. aeruginosa, with the exoT(+)exoS(+)exoU(+) genotype, that has not yet been described in Brazil to the best of our knowledge. This comprehensive analysis of resistance mechanisms to carbapenem and fluoroquinolones and their association with TTSS virulence genes, covering MDR P. aeruginosa in Brazil, is the largest reported to date. PMID:25596115

  1. Antibacterial activity in four marine crustacean decapods.

    PubMed

    Haug, Tor; Kjuul, Anita K; Stensvåg, Klara; Sandsdalen, Erling; Styrvold, Olaf B

    2002-05-01

    A search for antibacterial activity in different body-parts of Pandalus borealis (northern shrimp), Pagurus bernhardus (hermit crab), Hyas araneus (spider crab) and Paralithodes camtschatica (king crab) was conducted. Dried samples were extracted with 60% (v/v) acetonitrile, containing 0.1% (v/v) trifluoroacetic acid, and further extracted and concentrated on C18 cartridges. Eluates from the solid phase extraction were tested for antibacterial, lysozyme and haemolytic activity. Antibacterial activity against Escherichia coli, Vibrio anguillarum, Corynebacterium glutamicum and Staphylococcus aureus was detected in extracts from several tissues in all species tested, but mainly in the haemolymph and haemocyte extracts. V. anguillarum and C. glutamicum were generally the most sensitive micro-organisms. In P. borealis and P. bernhardus most of the active fractions were not affected by proteinase K treatment, while in H. araneus and P. camtschatica most fractions were sensitive to proteinase K treatment, indicating antibacterial factors of proteinaceous nature. In P. bernhardus the active fractions were generally heat labile, whereas in H. araneus the activities were resistant to heat. Differences between active extracts regarding hydrophobicity and sensitivity for heat and proteinase K treatment indicate that several compounds are responsible for the antibacterial activities detected. Lysozyme-like activity could be detected in some fractions and haemolytic activity against human red blood cells could be detected in haemolymph/haemocyte and exoskeleton extracts from all species tested. PMID:12194450

  2. Substitutions of Ser83Leu in GyrA and Ser80Leu in ParC Associated with Quinolone Resistance in Acinetobacter pittii.

    PubMed

    Gu, Dan-xia; Hu, Yun-jian; Zhou, Hong-wei; Zhang, Rong; Chen, Gong-xiang

    2015-06-01

    To investigate the prevalence and the mechanism of quinolone-resistant Acinetobacter pittii, 634 Acinetobacter calcoaceticus-Acinetobacter baumannii complex isolates were collected throughout Zhejiang Province. Identification of isolates was conducted by matrix-assisted laser desorption ionization/time of flight mass spectrometry (MALDI-TOF MS), blaOXA-51-like gene, and partial RNA polymerase ?-subunit (rpoB) amplification. Twenty-seven isolates of A. pittii were identified. Among the 634 isolates, A. baumannii, A. pittii, Acinetobacter nosocomialis, and A. calcoaceticus counted for 87.22%, 4.26%, 8.20%, and 0.32%, respectively. Antimicrobial susceptibility of nalidixic acid, ofloxacin, enoxacin, ciprofloxacin, lomefloxacin, levofloxacin, sparfloxacin, moxifloxacin, and gatifloxacin for 27 A. pittii were determined by the agar dilution method. Detection of quinolone-resistant determining regions of gyrA, gyrB, parC, and parE was performed for the A. pittii isolates. In addition, plasmid-mediated quinolone resistance (PMQR) determinants (qnrA, qnrB, qnrS, qnrC, qnrD, aac(6')-Ib-cr, qepA, oqxA, and oqxB) were investigated. All the 27 isolates demonstrated a higher minimum inhibitory concentration (MIC) to old quinolones than the new fluoroquinolones. No mutation in gyrA, gyrB, parC, or parE was detected in 20 ciprofloxacin-susceptible isolates. Seven ciprofloxacin-resistant A. pittii were identified with a Ser83Leu mutation in GyrA. Among them, six isolates with simultaneous Ser83Leu amino acid substitution in GyrA and Ser80Leu in ParC displayed higher MIC values against ciprofloxacin. Additionally, three were identified with a Met370Ile substitution in ParE, and two were detected with a Tyr317His mutation in ParE, which were reported for the first time. No PMQR determinants were identified in the 27 A. pittii isolates. In conclusion, mutations in chromosome play a major role in quinolone resistance in A. pittii, while resistance mechanisms mediated by plasmid have not been found. Ser83Leu substitution in GyrA and Ser80Leu substitution in ParC are associated with quinolone resistance in A. pittii. Whether Met370Ile and Tyr317His substitutions in ParE play a minor role requires further investigation. PMID:25514581

  3. Enhanced antibacterial effect of antibiotics in combination with silver nanoparticles against animal pathogens.

    PubMed

    Smekalova, Monika; Aragon, Virginia; Panacek, Ales; Prucek, Robert; Zboril, Radek; Kvitek, Libor

    2016-03-01

    Antibiotic resistant bacteria are a serious health risk in both human and veterinary medicine. Several studies have shown that silver nanoparticles (AgNPs) exert a high level of antibacterial activity against antibiotic resistant strains in humans. The aim of this study was to evaluate the antibacterial effects of a combined therapy of AgNPs and antibiotics against veterinary bacteria that show resistance to antibiotics. A microdilution checkerboard method was used to determine the minimal inhibitory concentrations of both types of antimicrobials, alone and in combination. The fractional inhibitory concentration index was calculated and used to classify observed collective antibacterial activity as synergistic, additive (only the sum of separate effects of drugs), indifferent (no effect) or antagonistic. From the 40 performed tests, seven were synergistic, 17 additive and 16 indifferent. None of the tested combinations showed an antagonistic effect. The majority of synergistic effects were observed for combinations of AgNPs given together with gentamicin, but the highest enhancement of antibacterial activity was found with combined therapy together with penicillin G against Actinobacillus pleuropneumoniae. A. pleuropneumoniae and Pasteurella multocida originally resistant to amoxycillin, gentamicin and colistin were sensitive to these antibiotics when combined with AgNPs. The study shows that AgNPs have potential as adjuvants for the treatment of animal bacterial diseases. PMID:26832810

  4. Improved small-molecule macroarray platform for the rapid synthesis and discovery of antibacterial chalcones.

    PubMed

    Stringer, Joseph R; Bowman, Matthew D; Weisblum, Bernard; Blackwell, Helen E

    2011-03-14

    Bacterial resistance to current antibiotics is a major global health threat. Consequently, there is an urgent need for the identification of new antibacterial agents. We are applying the small-molecule macroarray platform to rapidly synthesize and screen compounds for activity against methicillin-resistant Staphylococcus aureus (MRSA). Herein, we report the synthesis of a 1,3-diphenyl-2-propen-1-one (chalcone) macroarray using a Rink-amide linker-derivatized cellulose support. The Rink linker allowed for the incorporation of a broader array of library building blocks relative to our previous syntheses because milder reaction conditions could be utilized; significantly higher compound loadings were also achieved (~80% vs ~15%). Analysis of the 174-member chalcone macroarray in off-support antibacterial screening assays revealed three chalcones with minimum inhibitory concentration (MIC) values against MRSA comparable to currently used antibacterial drugs and low hemolytic activities. These results serve to further showcase and extend the utility of the small molecule macroarray for antibacterial discovery. PMID:21210707

  5. In vitro antibacterial activity of Hibiscus rosa-sinensis flower extract against human pathogens

    PubMed Central

    Ruban, P; Gajalakshmi, K

    2012-01-01

    Objective To access the in vitro antibacterial activity of Hibiscus rosa-sinensis (H. rosa- sinensis) flower extract against human pathogens. Methods Antibacterial activity was evaluated by using disc and agar diffusion methods. The protein was run through poly acrylmide gel electrophoresis to view their protein profile. Results The results showed that the cold extraction illustrates a maximum zone of inhibition against Bacillus subtillis (B. subtillis), Escherichia coli (E. coli) viz., (17.00 ± 2.91), (14.50 ± 1.71) mm, followed by hot extraction against, E. coli, Salmonella sp. as (11.66 ± 3.14), (10.60 ± 3.09) mm. In methanol extraction showed a highest zone of inhibition recorded against B. subtillis, E. coli as (18.86 ± 0.18), (18.00 ± 1.63) mm pursued by ethanol extraction showed utmost zone of inhibition recorded against Salmonella sp. at (20.40 ± 1.54) mm. The crude protein from flower showed a maximum inhibitory zone observed against Salmonella sp., E. coli viz., (16.55 ± 1.16), (14.30 ± 2.86) mm. The flower material can be taken as an alternative source of antibacterial agent against the human pathogens. Conclusions The extracts of the H. rosa-sinensis are proved to have potential antibacterial activity, further studies are highly need for the drug development. PMID:23569938

  6. Purification, characterization and antibacterial activity of L-amino acid oxidase from Cerastes cerastes.

    PubMed

    Hanane-Fadila, Ziad-Meziane; Fatima, Laraba-Djebari

    2014-08-01

    Antibiotic resistance presents a real problem in which new antibacterial molecules from natural secretions could be beneficial in the development of new drugs. In this study, Cerastes cerastes venom was investigated for its antibacterial activity against Gram-positive and Gram-negative bacteria. The antibacterial activity was evaluated by measuring the halo inhibition and minimum inhibitory concentration (MIC). An L-amino acid oxidase (CcLAAO) was purified from this venom using three chromatographic steps; its homogeneity (60 kDa) was confirmed by SDS-PAGE. LC-MS/MS analysis of CcLAAO showed similarities with other LAAO enzymes from Echis ocellatus and Viridovipera stejnegeri venoms. CcLAAO presents an antibacterial activity against three bacterial strains (Staphylococcus aureus, Methicillin-resistant S. aureus, and Pseudomonas aeruginosa) with MIC values of 10, 10, and 20 μg/mL, respectively. However, no effect was observed against Escherichia coli and yeast strains. Kinetic parameters of CcLAAO evaluated on L-leucine at pH 8.0 and 20°C were Km = 0.06 mmol and Vmax = 164 mmol/min. PMID:24817275

  7. Synthesis, characterization and antibacterial properties of dihydroxy quaternary ammonium salts with long chain alkyl bromides.

    PubMed

    Liu, Wen-Shuai; Wang, Chun-Hua; Sun, Ju-Feng; Hou, Gui-Ge; Wang, Yu-Peng; Qu, Rong-Jun

    2015-01-01

    Five N-methyl-N-R-N,N-bis(2-hydroxyethyl) ammonium bromides (R = -benzyl (chloride, BNQAS), -dodecyl (C12QAS), -tetradecyl (C14QAS), -hexadecyl (C16QAS), -octadecyl (C18QAS)) were prepared based on N-methyldiethanolamine (MDEA) and halohydrocarbon. Five QAS were characterized by FTIR, NMR, and MS. BNQAS, C12QAS, C14QAS, and C16QAS were confirmed by X-ray single-crystal diffraction. Their antibacterial properties indicated good antibacterial abilities against E. coli, S. aureus, B. subtilis, especially C12QAS with the best antibacterial ability (100% to E. coli, 95.65% to S. aureus, and 91.41% to B. subtilis). In addition, C12QAS also displayed the best antifungal activities than BNQAS and C18QAS against Cytospora mandshurica, Botryosphaeria ribis, Physalospora piricola, and Glomerella cingulata with the ratio of full marks. The strategy provides a facile way to design and develop new types of antibacterial drugs for application in preventing the fruit rot, especially apple. PMID:25215430

  8. In Vitro Study to Evaluate Antibacterial and Non-haemolytic Activities of Four Iranian Medicinal Plants

    PubMed Central

    Sepahi, S; Ghorani-Azam, A; Sepahi, S; Asoodeh, A; Rostami, S

    2014-01-01

    Objective: Aqueous extracts of four medicinal plants including Ferula gummosa, Echinophora orientalis, Nasturtium microphyllum and Verbascum thapsus were used to determine their antibacterial activities and minimum inhibitory concentration (MIC). The aim of this study was to assess antibacterial activity of extracts of four medicinal plants against a Gram-positive and a Gram-negative bacteria (Staphylococcus aureus PTCC1431, and Escherichia coli HP101BA 7601c). Methods: Radial diffusion assay was used to assess the antibacterial activity of extracted samples. Haemolysis assay was also used to examine their nontoxic effects on human red blood cells. Results: This study showed that all the mentioned plants have satisfactory antibacterial effects against both Gram-positive and Gram-negative bacteria. Minimum inhibitory concentration values of these samples were less than 750 μg/mL. In addition, no significant haemolytic activity was observed at their MIC values. Conclusion: The results of this study showed that all these studied plants have good potential for further studies for drug discovery. PMID:25429470

  9. Multifunctional biocompatible and biodegradable folic acid conjugated poly(ε-caprolactone)-polypeptide copolymer vesicles with excellent antibacterial activities.

    PubMed

    Wang, Mingzhi; Zhou, Chuncai; Chen, Jing; Xiao, Yufen; Du, Jianzhong

    2015-04-15

    Cancer patients after chemotherapy may also suffer bacterial attack due to badly decreased immunity. Although with high bacterial efficacy, conventional antibiotics are prone to inducement of drug resistance and may be not suitable for some cancer patients. In contrast, antibacterial peptides are highly effective in inhibiting bacteria without inducing resistance in pathogens. Presented in this article is a novel kind of highly effective antibacterial peptide-based biocompatible and biodegradable block copolymer vesicle. The copolymer is poly(ε-caprolactone)-block-poly[phenylalanine-stat-lysine-stat-(lysine-folic acid)] [PCL19-b-poly[Phe12-stat-Lys9-stat-(Lys-FA)6

  10. Unveiling the Mode of Action of Two Antibacterial Tanshinone Derivatives

    PubMed Central

    Wang, Dongdong; Zhang, Wuxia; Wang, Tingting; Li, Na; Mu, Haibo; Zhang, Jiwen; Duan, Jinyou

    2015-01-01

    In this study, 2-(N-pyrrolidine-alkyl) tanshinones bearing pyrrolidine groups were synthesized and the antibacterial mechanism was explored. These derivatives selectively elicited antibacterial activity against Gram-positive bacteria. Moreover, their antibacterial activities were time-, concentration-dependent and persistent. It appeared that Fenton-mediated hydroxyl radicals were involved, and the disruption of cell membranes was observed. This study indicates that 2-(N-pyrrolidine-alkyl) tanshinones might be potential candidates as antibacterial agents. PMID:26263982

  11. [Infectious diseases caused by carbapenemase-producing Enterobacteriaceae--a particular challenge for antibacterial therapy].

    PubMed

    Stock, Ingo

    2014-05-01

    Enterobacteriaceae species such as Escherichia coli and Klebsiella pneumoniae are among the most common human pathogens. They are responsible for a wide range of community-acquired and nosocomial diseases. Many of the illnesses caused by these bacteria could be treated with beta-lactams for several decades. The increasing use of carbapenems for the treatment of diseases caused by Enterobacteriaceae expressing extended spectrum beta-lactamases, however, lead to the selection and spread of carbapenemase-producing pathogens. Such bacteria are not only resistant to virtually all beta-lactams, but also to numerous other antibiotics such as quinolones, co-trimoxazole, nitrofurantoin, tetracyclines and most aminoglycosides. During the last years, carbapenemase-producing Enterobacteriaceae have spread into almost all regions of the world. Klebsiella pneumoniae carbapenemases (KPC, belonging to Ambler class A), OXA-48 enzymes and their derivatives (belonging to Ambler class D) as well as some metallo-beta-lactamases (Ambler class B) such as NDM, VIM and IMP are the most important carbapenemases produced by Enterobacteriaceae strains. In Germany, the metallo-carbapenemase GIM-1, which has never been proven in bacteria outside Germany, is also of clinical significance. There is no established antibacterial therapy for these difficult-to-treat diseases. For the treatment of severe diseases caused by carbapenemase-producing bacteria, fosfomycin, gentamicin and tigecycline, polymyxins such as polymyxin B or colistin as well as carbapenems, are frequently applied. Combination antibiotic treatment may be more effective than monotherapy for severe ill patients with serious diseases. The most promising new treatment options arise with the development of avibactam. This non-beta-lactam beta-lactamase inhibitor shows good activity against (nearly) all class A and class C beta-lactamases (including strains expressing class A carbapenemases and/or derepressed AmpC enzymes) as well as OXA-48 carbapenemases. It may be used successfully in combination with ceftazidime, ceftaroline or aztreonam. PMID:24908928

  12. A new antibacterial benzophenone glycoside from Psidium guajava (Linn.) leaves.

    PubMed

    Ukwueze, Stanley E; Osadebe, Patience O; Okoye, Festus B C

    2015-01-01

    Bioactivity-guided fractionation of methanol extract from the leaves of Psidium guajava L. (Myrtaceae) yielded a new benzophenone glycoside, Guajaphenone A (2) together with two known compounds, Garcimangosone D (1) and Guaijaverin (3). Their structures were elucidated by analysis of spectroscopic data including 1D and 2D NMR and electrospray ionisation mass spectrometry (ESI-MS). The isolated compounds were screened against standard strains of Gram-positive and Gram-negative bacteria using broth dilution assay method, and the MIC values determined and compared with reference antibiotic ceftriaxone. They were found to have significant antibacterial activities against Escherichia coli and Staphylococcus aureus with all of them showing better activities against S. aureus, but displaying weaker activities, in comparison to ceftriaxone. However, despite reduced effect of these compounds against the organisms, this work opens the perspective to use these molecules as 'leads' for the design of novel and selective drug candidates for some tropical infectious diseases. PMID:25631395

  13. A new antibacterial titanium-copper sintered alloy: preparation and antibacterial property.

    PubMed

    Zhang, Erlin; Li, Fangbing; Wang, Hongying; Liu, Jie; Wang, Chunmin; Li, Muqin; Yang, Ke

    2013-10-01

    Copper element was added in pure titanium by a powder metallurgy to produce a new antibacterial titanium-copper alloy (Ti-Cu alloy). This paper reported the very early stage results, emphasizing on the preparation, mechanical property and antibacterial activity. The phase constitution was analyzed by XRD and the microstructure was observed under SEM equipped with EDS. The hardness, the compressive strength and the corrosion resistance of Ti-Cu alloy were tested in comparison with cp-Ti. The antibacterial property of the Ti-Cu alloy was assessed by two methods: agar diffusion assay and plate-count method, in which Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) were used. XRD and SEM results showed that Ti2Cu phase and Cu-rich phase were synthesized in the Ti-Cu sintered alloy, which significantly increases the hardness and the compressive strength compared with cp-Ti and slightly improves the corrosion resistance. No antibacterial activity was detected by the agar diffusion assay on the Ti-Cu alloy, but the plate-count results indicated that the Ti-Cu alloy exhibited strong antibacterial property against both bacteria even after three polishing treatments, which demonstrates strongly that the whole alloy is of antibacterial activity. The antibacterial mechanism was thought to be in associated with the Cu ion released from the Ti-Cu alloy. PMID:23910344

  14. Antibacterial activity of eight Brazilian annonaceae plants.

    PubMed

    Takahashi, Jacqueline A; Pereira, Cássia R; Pimenta, Lúcia P S; Boaventura, Maria Amélia D; Silva, Luiz G F E

    2006-01-01

    Sixteen extracts, obtained from eight Brazilian plants of Annonaceae family, were screened for their antibacterial activity: Xylopia frutescens, X. aromatica, X. amazonica, X. benthamii, Annona ambotay, A. crassiflora, A. muricata and A. cherimolia. Amongst the investigated extracts, six showed antibacterial activity against at least one of the tested organisms at the concentration of 100 microg/mL. The most active extracts were those prepared from X. frutescens, X. amazonica, and A. ambotay. A phytochemical screening showed the presence of anonaceus acetogenins in some active extracts. Eleven diterpenoids were also tested for comparison purposes. Six were natural products, previously isolated from Xylopia sp. (kaurenoic, frutoic, xylopic, 15beta-hydroxy-kaurenoic and trachylobanic acids plus kaurenol) and five were derivatives of such compounds, obtained by esterification or reduction reactions. Trachylobanic acid showed antibacterial activity against B. subtilis and S. aureus. PMID:16286303

  15. Antibacterial nanofiber materials activated by light.

    PubMed

    Jesenská, Soňa; Plíštil, Lukáš; Kubát, Pavel; Lang, Kamil; Brožová, Libuše; Popelka, Stěpán; Szatmáry, Lórant; Mosinger, Jiří

    2011-12-15

    Electrospun polymeric nanofiber materials doped with 5,10,15,20-tetraphenylporphyrin (TPP) photosensitizer were prepared from four different polymers and were characterized with microscopic methods, steady-state, and time-resolved fluorescence and absorption spectroscopy. The polymers used included polyurethane Larithane™ (PUR), polystyrene (PS), polycaprolactone (PCL), and polyamide 6 (PA6). The antibacterial activity of all nanofiber materials against E. coli was activated by visible light and it was dependent on oxygen permeability/diffusion coefficients and the diameter of the polymeric nanofibers. This activity is based on oxidation ability of singlet oxygen O₂(¹Δ(g)) that is generated upon irradiation. All tested nanofiber materials exhibited prolonged antibacterial properties, even in the dark after long-duration irradiation. The post-irradiation effect was explained by the photogeneration of H₂O₂, which provided the material with long-lasting antibacterial properties. PMID:21972201

  16. Antibacterial Resistance Leadership Group: Open for Business

    PubMed Central

    Chambers, Henry F.; Bartlett, John G.; Bonomo, Robert A.; Chiou, Christine; Cosgrove, Sara E.; Cross, Heather R.; Daum, Robert S.; Downing, Michele; Evans, Scott R.; Knisely, Jane; Kreiswirth, Barry N.; Lautenbach, Ebbing; Mickley, Brenda S.; Patel, Robin; Pettigrew, Melinda M.; Rodvold, Keith A.; Spellberg, Brad; Fowler, Vance G.

    2014-01-01

    Funded by the National Institute of Allergy and Infectious Diseases, the Antibacterial Resistance Leadership Group (ARLG) is tasked with developing a clinical research agenda and conducting clinical studies to address the growing public health threat of antibacterial resistance. The ARLG has identified 4 high-priority areas of research: infections caused by gram-negative bacteria, infections caused by gram-positive bacteria, antimicrobial stewardship and infection prevention, and diagnostics. The ARLG will be accepting proposals from the scientific community for clinical research that addresses 1 or more of these high-priority areas. These studies should have the potential to transform medical practice and be unlikely to occur without ARLG support. The purpose of this article is to make interested parties aware of clinical research opportunities made available by ARLG and to encourage submission of clinical research proposals that address the problem of antibacterial resistance. PMID:24610430

  17. Antibacterial household products: cause for concern.

    PubMed Central

    Levy, S. B.

    2001-01-01

    The recent entry of products containing antibacterial agents into healthy households has escalated from a few dozen products in the mid-1990s to more than 700 today. Antibacterial products were developed and have been successfully used to prevent transmission of disease-causing microorganisms among patients, particularly in hospitals. They are now being added to products used in healthy households, even though an added health benefit has not been demonstrated. Scientists are concerned that the antibacterial agents will select bacteria resistant to them and cross-resistant to antibiotics. Moreover, if they alter a person's microflora, they may negatively affect the normal maturation of the T helper cell response of the immune system to commensal flora antigens; this change could lead to a greater chance of allergies in children. As with antibiotics, prudent use of these products is urged. Their designated purpose is to protect vulnerable patients. PMID:11485643

  18. Cytotoxic and antibacterial effects of orthodontic appliances.

    PubMed

    Grimsdottir, M R; Hensten-Pettersen, A

    1993-08-01

    The cytotoxic and antibacterial effects of orthodontic appliances were assessed. Metallic devices used in orthodontics, such as molar bands, brackets, and archwires were tested by the agar overlay cytotoxicity test with mouse fibroblast cells. The same devices were tested for antibacterial effect with Streptococcus mutans and S. sanguis. The multicomponent devices, which are bonded with silver- and copper-based brazing alloys, were more cytotoxic than the single-component devices, probably because copper is more cytotoxic than nickel. The devices had a definite, but low, antibacterial effect, as compared with the 0.05% chlorhexidine positive control. A cytotoxic effect of the devices per se might contribute to a localized gingivitis. It is uncertain whether orthodontic devices have any significant inhibitory effect on dental plaque viability. PMID:8362202

  19. Injectable Bioadhesive Hydrogels with Innate Antibacterial Properties

    PubMed Central

    Giano, Michael C.; Ibrahim, Zuhaib; Medina, Scott H.; Sarhane, Karim A.; Christensen, Joani M.; Yamada, Yuji; Brandacher, Gerald; Schneider, Joel P.

    2014-01-01

    Surgical site infections cause significant postoperative morbidity and increased healthcare costs. Bioadhesives used to fill surgical voids and support wound healing are typically devoid of antibacterial activity. Here, we report novel syringe-injectable bioadhesive hydrogels with inherent antibacterial properties prepared from mixing polydextran aldehyde (PDA) and branched polyethylenimine (PEI). These adhesives kill both Gram-negative and Gram–positive bacteria, while sparing human erythrocytes. An optimal composition of 2.5 wt % oxidized dextran and 6.9 wt % PEI sets within seconds forming a mechanically rigid (~1700 Pa) gel offering a maximum adhesive stress of ~ 2.8 kPa. A murine infection model showed that the adhesive is capable of killing S. pyogenes introduced subcutaneously at the bioadhesive’s surface, with minimal inflammatory response. The adhesive was also effective in a cecal ligation and puncture model, preventing sepsis and significantly improving survival. These bioadhesives represent novel, inherently antibacterial materials for wound filling applications. PMID:24958189

  20. Actinopyga lecanora Hydrolysates as Natural Antibacterial Agents

    PubMed Central

    Ghanbari, Raheleh; Ebrahimpour, Afshin; Abdul-Hamid, Azizah; Ismail, Amin; Saari, Nazamid

    2012-01-01

    Actinopyga lecanora, a type of sea cucumber commonly known as stone fish with relatively high protein content, was explored as raw material for bioactive peptides production. Six proteolytic enzymes, namely alcalase, papain, pepsin, trypsin, bromelain and flavourzyme were used to hydrolyze A. lecanora at different times and their respective degrees of hydrolysis (DH) were calculated. Subsequently, antibacterial activity of the A. lecanora hydrolysates, against some common pathogenic Gram positive bacteria (Bacillus subtilis and Staphylococcus aureus) and Gram negative bacteria (Escherichia coli, Pseudomonas aeruginosa, and Pseudomonas sp.) were evaluated. Papain hydrolysis showed the highest DH value (89.44%), followed by alcalase hydrolysis (83.35%). Bromelain hydrolysate after one and seven hours of hydrolysis exhibited the highest antibacterial activities against Pseudomonas sp., P. aeruginosa and E. coli at 51.85%, 30.07% and 30.45%, respectively compared to the other hydrolysates. Protein hydrolysate generated by papain after 8 h hydrolysis showed maximum antibacterial activity against S. aureus at 20.19%. The potent hydrolysates were further fractionated using RP-HPLC and antibacterial activity of the collected fractions from each hydrolysate were evaluated, wherein among them only three fractions from the bromelain hydrolysates exhibited inhibitory activities against Pseudomonas sp., P. aeruginosa and E. coli at 24%, 25.5% and 27.1%, respectively and one fraction of papain hydrolysate showed antibacterial activity of 33.1% against S. aureus. The evaluation of the relationship between DH and antibacterial activities of papain and bromelain hydrolysates revealed a meaningful correlation of four and six order functions. PMID:23222684

  1. Injectable bioadhesive hydrogels with innate antibacterial properties

    NASA Astrophysics Data System (ADS)

    Giano, Michael C.; Ibrahim, Zuhaib; Medina, Scott H.; Sarhane, Karim A.; Christensen, Joani M.; Yamada, Yuji; Brandacher, Gerald; Schneider, Joel P.

    2014-06-01

    Surgical site infections cause significant postoperative morbidity and increased healthcare costs. Bioadhesives used to