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Sample records for quinolone antibacterial drug

  1. On the mechanism of action of quinolone drugs.

    PubMed

    Palumbo, M; Gatto, B; Zagotto, G; Palù, G

    1993-09-01

    Antibacterial quinolones are thought to inhibit DNA gyrase by trapping the enzyme as a complex with the DNA substrate. The precise molecular details of drug-DNA and drug-enzyme interactions remain controversial. Here, a model is proposed that accounts for the influence of magnesium ions on quinolone-DNA binding. PMID:8137121

  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

  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. Mechanisms of drug resistance: quinolone resistance

    PubMed Central

    Hooper, David C.; Jacoby, George A.

    2015-01-01

    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

  5. A “Double-Edged” Scaffold: Antitumor Power within the 
Antibacterial Quinolone

    PubMed Central

    Bisacchi, Gregory S.; Hale, Michael R.

    2016-01-01

    In the late 1980s, reports emerged describing experimental antibacterial quinolones having significant potency against eukaryotic Type II topoisomerases (topo II) and showing cytotoxic activity against tumor cell lines. As a result, several pharmaceutical companies initiated quinolone anticancer programs to explore the potential of this class in comparison to conventional human topo II inhibiting antitumor drugs such as doxorubicin and etoposide. In this review, we present a modern re-evaluation of the anticancer potential of the quinolone class in the context of today’s predominantly pathway-based (rather than cytotoxicity-based) oncology drug R&D environment. The quinolone eukaryotic SAR is comprehensively discussed, contrasted with the corresponding prokaryotic data, and merged with recent structural biology information which is now beginning to help explain the basis for that SAR. Quinolone topo II inhibitors appear to be much less susceptible to efflux-mediated resistance, a current limitation of therapy with conventional agents. Recent advances in the biological understanding of human topo II isoforms suggest that significant progress might now be made in overcoming two other treatment-limiting disadvantages of conventional topo II inhibitors, namely cardiotoxicity and drug-induced secondary leukemias. We propose that quinolone class topo II inhibitors could have a useful future therapeutic role due to the continued need for effective topo II drugs in many cancer treatment settings, and due to the recent biological and structural advances which can now provide, for the first time, specific guidance for the design of a new class of inhibitors potentially superior to existing agents. PMID:26695512

  6. Inhibitory potency of quinolone antibacterial agents against cytochrome P450IA2 activity in vivo and in vitro.

    PubMed Central

    Fuhr, U; Anders, E M; Mahr, G; Sörgel, F; Staib, A H

    1992-01-01

    Inhibition of cytochrome P450IA2 activity is an important adverse effect of quinolone antibacterial agents. It results in a prolonged half-life for some drugs that are coadministered with quinolones, such as theophylline. The objective of the study described here was to define the parameters for quantifying the inhibitory potencies of quinolones against cytochrome P450IA2 in vivo and in vitro and to investigate the relationship between the results of both approaches. Cytochrome P450IA2 activity in vitro was measured by using the 3-demethylation rate of caffeine (500 microM) in human liver microsomes. The inhibitory potency of a quinolone in vitro was determined by calculating the decrease in the activity of cytochrome P450IA2 caused by addition of the quinolone (500 microM) into the incubation medium. The mean values (percent reduction of activity without quinolone) were as follows: enoxacin, 74.9%; ciprofloxacin, 70.4%; nalidixic acid, 66.6%; pipemidic acid, 59.3%; norfloxacin, 55.7%; lomefloxacin, 23.4%; pefloxacin, 22.0%; amifloxacin, 21.4%; difloxacin, 21.3%; ofloxacin, 11.8%; temafloxacin, 10.0%; fleroxacin, no effect. The inhibitory potency of a quinolone in vivo was defined by a dose- and bioavailability-normalized parameter calculated from changes of the elimination half-life of theophylline and/or caffeine reported in previously published studies. Taking the pharmacokinetics of the quinolones into account, it was possible to differentiate between substances with and without clinically relevant inhibitory effects by using results of in vitro investigations. The in vitro test described here may help to qualitatively predict the relevant drug interactions between quinolones and methylxanthines that occur during therapy. PMID:1510417

  7. Design, synthesis, antibacterial evaluation and docking study of novel 2-hydroxy-3-(nitroimidazolyl)-propyl-derived quinolone.

    PubMed

    Li, Qing; Xing, Junhao; Cheng, Haibo; Wang, Hui; Wang, Jing; Wang, Shuai; Zhou, Jinpei; Zhang, Huibin

    2015-01-01

    A novel series of 2-hydroxy-3-(nitroimidazolyl)-propyl-derived quinolones 6a-o were synthesized and evaluated for their in vitro antibacterial activity. Most of the target compounds exhibited potent activity against Gram-positive strains. Among them, moxifloxacin analog 6n displayed the most potent activity against Gram-positive strains including S. epidermidis (MIC = 0.06 μg/mL), MSSE (MIC = 0.125 μg/mL), MRSE (MIC = 0.03 μg/mL), S. aureus (MIC = 0.125 μg/mL), MSSA (MIC = 0.125 μg/mL), (MIC = 2 μg/mL). Its activity against MRSA was eightfold more potent than reference drug gatifloxacin. Finally, docking study of the target compound 6n revealed that the binding model of quinolone nucleus was similar to that of gatifloxacin and the 2-hydroxy-3-(nitroimidazolyl)-propyl group formed two additional hydrogen bonds. PMID:25048811

  8. Characterization of quinolone antibacterial-induced convulsions and increases in nuclear AP-1 DNA- and CRE-binding activities in mouse brain.

    PubMed

    Ito, Y; Ishige, K; Aizawa, M; Fukuda, H

    1999-05-01

    The quinolone antibacterials enoxacin and norfloxacin (2.5 mg/kg, i.v.) provoked clonic convulsions in mice treated concomitantly with biphenylacetic acid (BPAA, 100 mg/kg, i.p.), a major metabolite of the nonsteroidal anti-inflammatory drug fenbufen. Gel-shift assays showed that enoxacin-induced convulsions resulted in increases in nuclear activator protein 1 (AP-1) DNA- and cyclic AMP responsive element (CRE)-binding activities in the cerebral cortex and hippocampus, but not in other regions, such as the cerebellum and thalamus. In contrast, ofloxacin and levofloxacin, at the same doses, in the presence of BPAA did not evoke convulsions or increase these DNA-binding activities. Administration of these quinolones and BPAA alone elicited neither convulsions nor increases in these DNA-binding activities. These results suggest that the increased nuclear AP-1 DNA- and CRE-binding activities in the cerebral cortex and hippocampus induced by quinolones with BPAA correlated with seizure activities and that these brain regions play pivotal roles in quinolone-induced convulsions. PMID:10340309

  9. Simultaneous determination of quinolone antibacterials in bovine milk by liquid chromatography-mass spectrometry.

    PubMed

    Zafra-Gómez, Alberto; Garballo, Antonio; Ballesteros, Oscar; Navalón, Alberto; García-Ayuso, Luís E

    2008-11-01

    A new liquid chromatography-mass spectrometry (LC-MS) method has been developed and validated for the simultaneous determination of eight quinolone antibacterials for veterinary use in processed bovine milk samples. The quinolones studied included marbofloxacin, ciprofloxacin, danofloxacin, enrofloxacin, sarafloxacin, difloxacin, oxolinic acid and flumequine. Also, a new sample-treatment procedure was used for extraction and preconcentration of these compounds. It involved defatting by centrifugation, protein precipitation by adding a mixture of glacial acetic acid-acetonitrile and removing acetonitrile with dichloromethane; finally, the acidified aqueous layer was evaporated to dryness in a speed vac system, resuspended in the mobile phase and filtered prior to LC injection. The mobile phase was composed of a formic acid aqueous solution 0.1% (v/v) and acetonitrile, with an initial composition of water-acetonitrile 95: 5 (v/v) and using linear gradient elution. Norfloxacin was used as internal standard. The limits of quantification found (2-7 ng g(-1)) were in all cases lower than the maximum residue limits tolerated by the European Union for these compounds in milk. PMID:18651586

  10. Physicochemical Studies and Anticancer Potency of Ruthenium η6-p-Cymene Complexes Containing Antibacterial Quinolones

    PubMed Central

    2011-01-01

    With the aim of exploring the anticancer properties of organometallic compounds with bioactive ligands, Ru(arene) compounds of the antibacterial quinolones nalidixic acid (2) and cinoxacin (3) were synthesized, and their physicochemical properties were compared to those of chlorido(η6-p-cymene)(ofloxacinato-κ2O,O)ruthenium(II) (1). All compounds undergo a rapid ligand exchange reaction from chlorido to aqua species. 2 and 3 are significantly more stable than 1 and undergo minor conversion to an unreactive [(cym)Ru(μ-OH)3Ru(cym)]+ species (cym = η6-p-cymene). In the presence of human serum albumin 1−3 form adducts with this transport protein within 20 min of incubation. With guanosine 5′-monophosphate (5′-GMP; as a simple model for reactions with DNA) very rapid reactions yielding adducts via its N7 atom were observed, illustrating that DNA is a possible target for this compound class. A moderate capacity of inhibiting tumor cell proliferation in vitro was observed for 1 in CH1 ovarian cancer cells, whereas 2 and 3 turned out to be inactive. PMID:21552495

  11. 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

  12. 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

  13. 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

  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. 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

  16. Indomethacin/ibuprofen-like anti-inflammatory agents selectively potentiate the gamma-aminobutyric acid-antagonistic effects of several norfloxacin-like quinolone antibacterial agents on [35S]t-butylbicyclophosphorothionate binding.

    PubMed

    Squires, R F; Saederup, E

    1993-05-01

    Four piperazinoquinolone antibacterial drugs (norfloxacin, ciprofloxacin, enoxacin, and pipemidic acid), known to be gamma-aminobutyric acid (GABA) antagonists, fully reversed the inhibitory effect of GABA on [35S]t-butylbicyclophosphorothionate ([35S] TBPS) binding to rat brain membranes in vitro. Twelve indomethacin/ibuprofen-like arylalkanoic acid (AAA) anti-inflammatory drugs alone had no effect on [35S]TBPS binding, or on its inhibition by GABA, but potentiated the GABA-antagonistic effects of the four quinolones. Felbinac (4-biphenylacetic acid) was most potent in this respect (EC50 = 110 nM, together with 5 microM norfloxacin), followed by flurbiprofen > anirolac > metiazinic acid > tolmetin = ketoprofen = fenbufen = indomethacin > fenoprofen > ibuprofen = (+)-naproxen = sulindac. Other anti-inflammatory analgesic drugs, including aspirin, diclofenac, diflunisal, meclofenamic acid, mefenamic acid, nambumetone, phenacetin, piroxicam, and phenylbutazone, failed to potentiate the GABA-antagonistic effect of norfloxacin. Felbinac (1 microM) increased the GABA-antagonistic potencies of norfloxacin and enoxacin about 26-fold, while increasing those of ciprofloxacin and pipemidic acid 7-fold and 2.3-fold, respectively. Using subsaturating concentrations of the four quinolones, concentration-response curves for felbinac yielded EC50 values ranging from 110 nM with 5 microM norfloxacin to 1.3 microM with 100 microM pipemidic acid. Three other piperazinoquinolone antibacterial agents (amifloxacin, difloxacin, and fleroxacin) and four nonpiperazinoquinolone anti-bacterial agents (oxolinic acid, cinoxacin, nalidixic acid, and piromidic acid) were much weaker GABA antagonists and were not significantly potentiated by felbinac. All other known GABAA receptor blockers tested, including R 5135, pitrazepin, bicuculline, SR 95531, strychnine, D-tubocurarine, thebaine, securinine, theophylline, and caffeine, were not potentiated by felbinac. Our results suggest that

  17. Mechanism of action of and resistance to quinolones

    PubMed Central

    Fàbrega, Anna; Madurga, Sergi; Giralt, Ernest; Vila, Jordi

    2009-01-01

    Summary Fluoroquinolones are an important class of wide‐spectrum antibacterial agents. The first quinolone described was nalidixic acid, which showed a narrow spectrum of activity. The evolution of quinolones to more potent molecules was based on changes at positions 1, 6, 7 and 8 of the chemical structure of nalidixic acid. Quinolones inhibit DNA gyrase and topoisomerase IV activities, two enzymes essential for bacteria viability. The acquisition of quinolone resistance is frequently related to (i) chromosomal mutations such as those in the genes encoding the A and B subunits of the protein targets (gyrA, gyrB, parC and parE), or mutations causing reduced drug accumulation, either by a decreased uptake or by an increased efflux, and (ii) quinolone resistance genes associated with plasmids have been also described, i.e. the qnr gene that encodes a pentapeptide, which blocks the action of quinolones on the DNA gyrase and topoisomerase IV; the aac(6′)‐Ib‐cr gene that encodes an acetylase that modifies the amino group of the piperazin ring of the fluoroquinolones and efflux pump encoded by the qepA gene that decreases intracellular drug levels. These plasmid‐mediated mechanisms of resistance confer low levels of resistance but provide a favourable background in which selection of additional chromosomally encoded quinolone resistance mechanisms can occur. PMID:21261881

  18. 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

  19. In vitro and in vivo antibacterial activities of CS-940, a new 6-fluoro-8-difluoromethoxy quinolone.

    PubMed

    Masuda, N; Takahashi, Y; Otsuki, M; Ibuki, E; Miyoshi, H; Nishino, T

    1996-05-01

    The in vitro and in vivo activities of CS-940, a new 6-fluoro-8-difluoromethoxy quinolone, were compared with those of ciprofloxacin, tosufloxacin, sparfloxacin, and levofloxacin. The in vitro activity of CS-940 against gram-positive bacteria was nearly equal to or greater than those of the other quinolones tested. In particular, CS-940 was two to eight times more active against methicillin-resistant Staphylococcus aureus than the other quinolones, at the MIC at which 90% of the clinical isolates are inhibited. Against gram-negative bacteria, the activity of CS-940 was comparable to or greater than those of tosufloxacin, sparfloxacin, and levofloxacin, while it was lower than that of ciprofloxacin. The activity of CS-940 was largely unaffected by medium, inoculum size, or the addition of horse serum, but it was decreased under acidic conditions, as was also seen with the other quinolones tested. CS-940 showed potent bactericidal activity against S. aureus, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. In oral treatment of mouse systemic infections caused by S. aureus, Streptococcus pneumoniae, Streptococcus pyogenes, E. coli, K. pneumoniae, Serratia marcescens, and P. aeruginosa, CS-940 was more effective than ciprofloxacin, sparfloxacin, and levofloxacin against all strains tested. Against experimental pneumonia with K. pneumoniae in mice, CS-940 was the most effective of all the quinolones tested. These results suggest that CS-940 may be effective in the therapy of various bacterial infections. PMID:8723467

  20. Nanofibers based antibacterial drug design, delivery and applications.

    PubMed

    Ulubayram, Kezban; Calamak, Semih; Shahbazi, Reza; Eroglu, Ipek

    2015-01-01

    Infections caused by microorganisms like bacteria, fungi, etc. are the main obstacle in healing processes. Conventional antibacterial administration routes can be listed as oral, intravenous/intramuscular, topical and inhalation. These kinds of drug administrations are faced with critical vital issues such as; more rapid delivery of the drug than intended which can result in bacterial resistance, dose related systemic toxicity, tissue irritation and finally delayed healing process that need to be tackled. Recently, studies have been focused on new drug delivery systems, overcoming resistance and toxicological problems and finally localizing the molecules at the site of action in a proper dose. In this regard, many nanotechnological approaches such as nanoparticulate therapeutic systems have been developed to address accompanying problems mentioned above. Among them, drug loaded electrospun nanofibers propose main advantages like controlled drug delivery, high drug loading capacity, high encapsulation efficiency, simultaneous delivery of multiple drugs, ease of production and cost effectiveness for pharmaceutical and biomedical applications. Therefore, some particular attention has been devoted to the design of electrospun nanofibers as promising antibacterial drug carrier systems. A variety of antibacterials e.g., biocides, antibiotics, quaternary ammonium salts, triclosan, metallic nanoparticles (silver, titanium dioxide, and zinc oxide) and antibacterial polymers (chitosan, polyethyleneimine, etc.) have been impregnated by various techniques into nanofibers that exhibit strong antibacterial activity in standard assays. This review highlights the design and delivery of antibacterial drug loaded nanofibers with particular focus on their function in the fields of drug delivery, wound healing, tissue engineering, cosmetics and other biomedical applications. PMID:25732666

  1. 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

  2. Multiresidue method for simultaneous determination of quinolone antibacterials in pig kidney samples by liquid chromatography with fluorescence detection.

    PubMed

    Hassouan, M K; Ballesteros, O; Zafra, A; Vílchez, J L; Navalón, A

    2007-11-15

    A new analytical method for simultaneous determination of eight quinolones namely, ciprofloxacin, danofloxacin, difloxacin, enrofloxacin, flumequine, marbofloxacin, oxolinic acid and sarafloxacin, in pig kidney samples was developed. The procedure involves the extraction of the quinolones from the samples by traditional extraction, a step for clean-up and preconcentration of the analytes by solid-phase extraction (SPE) and subsequent liquid chromatography separation with fluorescence detection (LC-FD). The mobile phase was composed of acetonitrile and 10 mM citrate buffer solution of pH 4.5, with an initial composition of acetonitrile-water 12:88 (v/v) and using linear gradient elution. Norfloxacin was used as internal standard. The limits of detection (1-8 microg kg(-1)) and the limits of quantification (5-27 microg kg(-1)) found were lower than the maximum residue limits regulated by the European Union for these compounds in pig kidney. PMID:17951118

  3. Application of SBDD to the discovery of new antibacterial drugs.

    PubMed

    Finn, John

    2012-01-01

    The emergence of bacteria that are multiply resistant to commonly used antibiotics has created the medical need for novel classes of antibacterial agents. The unique challenges to the discovery of new antibacterial drugs include the following: spectrum, selectivity, low emergence of new resistance, and high potency. With the emergence of genomic information, dozens of antibacterial targets have been pursued over the last 2 decades often using SBDD. This chapter reviews the application of structure-based drug design approaches on a selected group of antibacterial targets (DHFR, DHNA, PDF, and FabI) where significant progress has been made. We compare and contrast the different approaches and evaluate the results in terms of the biological profiles of the leads produced. Several common themes have emerged from this survey, resulting in a set of recommendations. PMID:22222458

  4. Inhibition of GABAA receptor-mediated current responses by enoxacin (new quinolone) and felbinac (non-steroidal anti-inflammatory drug) in Xenopus oocytes injected with mouse-brain messenger RNA.

    PubMed

    Kawakami, J; Shimokawa, M; Yamamoto, K; Sawada, Y; Asanuma, A; Yanagisawa, K; Iga, T

    1993-07-01

    The convulsant interaction between enoxacin (ENX), a new quinolone antibacterial agent (NQ), and felbinac (FLB), a non-steroidal anti-inflammatory drug (NSAID), in vivo was reproduced as the change of GABA-induced current response in Xenopus oocytes injected with mouse brain mRNA. GABA (10 microM) response was inhibited by ENX in a dose-dependent manner, and IC50 of ENX was 96 microM. Moreover, the inhibitory effect of ENX was 80-fold potentiated in the presence of 10 microM FLB. The GABAA-antagonistic interaction between these two drugs in vitro was considered a possible mechanism of convulsant reaction after concomitant administration of NQs and NSAIDs in vivo. PMID:7691340

  5. 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

  6. 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 (C(max)) 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. PMID:26590007

  7. 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

  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. Inhibitory effect of quinolone antimicrobial and nonsteroidal anti-inflammatory drugs on a medium chain acyl-CoA synthetase.

    PubMed

    Kasuya, F; Hiasa, M; Kawai, Y; Igarashi, K; Fukui, M

    2001-08-01

    The inhibitory effects of quinolone antimicrobial agents and nonsteroidal anti-inflammatory drugs on purified mouse liver mitochondrial medium chain acyl-CoA synthetase catalyzing the first reaction of glycine conjugation were examined, using hexanoic acid as a substrate. Enoxacin, ofloxacin, nalidixic acid, diflunisal, salicylic acid, 2-hydroxynaphthoic acid, and 2-hydroxydodecanoic acid, which do not act as substrates, were potent inhibitors. Diflunisal, nalidixic acid, salicylic acid, 2-hydroxynaphthoic acid, and 2-hydroxydodecanoic acid inhibited competitively this medium chain acyl-CoA synthetase with K(i) values of 0.6, 12.4, 19.6, 13.4, and 15.0 microM, respectively. Enoxacin and ofloxacin inhibited this medium chain acyl-CoA synthetase in a mixed-type manner with K(i) values of 23.7 and 38.2 microM, respectively. Felbinac, which is a substrate, inhibited the activity of this medium chain acyl-CoA synthetase for hexanoic acid (IC50 = 25 microM). The concomitant presence of enoxacin and felbinac strongly inhibited this medium chain acyl-CoA synthetase. These findings indicate that medium chain acyl-CoA synthetases may be influenced by quinolone antimicrobial and nonsteroidal anti-inflammatory drugs. PMID:11434910

  10. New natural products as new leads for antibacterial drug discovery.

    PubMed

    Brown, Dean G; Lister, Troy; May-Dracka, Tricia L

    2014-01-15

    Natural products have been a rich source of antibacterial drugs for many decades, but investments in this area have declined over the past two decades. The purpose of this review article is to provide a recent survey of new natural product classes and the mechanisms by which they work. PMID:24388805

  11. Potent in vitro antibacterial activity of DS-8587, a novel broad-spectrum quinolone, against Acinetobacter baumannii.

    PubMed

    Higuchi, Saito; Onodera, Yoshikuni; Chiba, Megumi; Hoshino, Kazuki; Gotoh, Naomasa

    2013-04-01

    We investigated the in vitro activity of DS-8587, a novel fluoroquinolone, against Acinetobacter baumannii. The MICs of DS-8587 against clinical isolates and its inhibitory activity against target enzymes were superior to those of ciprofloxacin and levofloxacin. Furthermore, the antibacterial activity of DS-8587 was less affected by adeA/adeB/adeC or abeM efflux pumps than was that of ciprofloxacin and the frequency of single-step mutations with DS-8587 was lower than that with ciprofloxacin. DS-8587 might be an effective agent against A. baumannii infection. PMID:23380726

  12. Potent In Vitro Antibacterial Activity of DS-8587, a Novel Broad-Spectrum Quinolone, against Acinetobacter baumannii

    PubMed Central

    Onodera, Yoshikuni; Chiba, Megumi; Hoshino, Kazuki; Gotoh, Naomasa

    2013-01-01

    We investigated the in vitro activity of DS-8587, a novel fluoroquinolone, against Acinetobacter baumannii. The MICs of DS-8587 against clinical isolates and its inhibitory activity against target enzymes were superior to those of ciprofloxacin and levofloxacin. Furthermore, the antibacterial activity of DS-8587 was less affected by adeA/adeB/adeC or abeM efflux pumps than was that of ciprofloxacin and the frequency of single-step mutations with DS-8587 was lower than that with ciprofloxacin. DS-8587 might be an effective agent against A. baumannii infection. PMID:23380726

  13. 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.

  14. Effect of bile duct ligation and unilateral nephrectomy on brain concentration and convulsant potential of the quinolone antibacterial agent levofloxacin in rats.

    PubMed

    Akahane, K; Ohkawara, S; Nomura, M; Kato, M

    1996-02-01

    To mimic the excretion route of the quinolone antibacterial agent levofloxacin (LVFX) in humans, we produced an excretion-limited (EL) model in male Sprague-Dawley rats by bile duct ligation and unilateral nephrectomy. We then examined the relationship between brain levels of LVFX and its convulsant effects in control and EL animals. Serum concentrations of LVFX in EL animals (EL + LVFX) were 2.38- and 1.59-fold and brain concentrations were 1.33- and 1.19-fold those of the controls (control + LVFX) at 30 min after a single intravenous injection of 10 and 100 mg/kg LVFX, respectively. Furthermore EL animals became more susceptible to the convulsant effect of LVFX with a 1.28-fold decrease in convulsion-inducing dose. In combination with oral pretreatment with 400 mg/kg 4-biphenylacetic acid (BPAA), convulsion-inducing doses in the control (control + LVFX + BPAA) and EL (EL + LVFX + BPAA) groups were markedly decreased by 2.25 and 9 times that of the control + LVFX group. EL operation and BPAA pretreatment slowed the elimination of LVFX in the serum and brain 4 hr later in the following order: EL + LVFX + BPAA, control + LVFX + BPAA, EL + LVFX, and control + LVFX groups. This order reflects that for the convulsion-inducing doses. These results suggest that EL rats may be a useful model for humans and that the convulsant effect of LVFX with or without BPAA arises not only from the attainment of maximum brain concentration but also from delayed disappearance from the brain. PMID:8742326

  15. Macrolide antibacterials. Drug interactions of clinical significance.

    PubMed

    von Rosensteil, N A; Adam, D

    1995-08-01

    Macrolide antibiotics can interact adversely with commonly used drugs, usually by altering metabolism due to complex formation and inhibition of cytochrome P-450 IIIA4 (CYP3A4) in the liver and enterocytes. In addition, pharmacokinetic drug interactions with macrolides can result from their antibiotic effect on microorganisms of the enteric flora, and through enhanced gastric emptying due to a motilin-like effect. Macrolides may be classified into 3 different groups according to their affinity for CYP3A4, and thus their propensity to cause pharmacokinetic drug interactions. Troleandomycin, erythromycin and its prodrugs decrease drug metabolism and may produce drug interactions (group 1). Others, including clarithromycin, flurithromycin, midecamycin, midecamycin acetate (miocamycin; ponsinomycin), josamycin and roxithromycin (group 2) rarely cause interactions. Azithromycin, dirithromycin, rikamycin and spiramycin (group 3) do not inactivate CYP3A4 and do not engender these adverse effects. Drug interactions with carbamazepine, cyclosporin, terfenadine, astemizole and theophylline represent the most frequently encountered interactions with macrolide antibiotics. If the combination of a macrolide and one of these compounds cannot be avoided, serum concentrations of concurrently administered drugs should be monitored and patients observed for signs of toxicity. Rare interactions and those of dubious clinical importance are those with alfentanil and sufentanil, antacids and cimetidine, oral anticoagulants, bromocriptine, clozapine, oral contraceptive steroids, digoxin, disopyramide, ergot alkaloids, felodipine, glibenclamide (glyburide), levodopa/carbidopa, lovastatin, methylprednisolone, phenazone (antipyrine), phenytoin, rifabutin and rifampicin (rifampin), triazolam and midazolam, valproic acid (sodium valproate) and zidovudine. PMID:7576262

  16. A Review for the Analysis of Antidepressant, Antiepileptic and Quinolone Type Drugs in Pharmaceuticals and Environmental Samples.

    PubMed

    Rani, Susheela; Malik, Ashok Kumar; Kaur, Ramandeep; Kaur, Ripneel

    2016-09-01

    The analysis of drugs in various biological fluids is an important criterion for the determination of the physiological performance of a drug. After sampling of the biological fluid, the next step in the analytical process is sample preparation. Sample preparation is essential for isolation of desired components from complex biological matrices and greatly influences their reliable and accurate determination. The complexity of biological fluids adds to the challenge of direct determination of the drug by chromatographic analysis, therefore demanding a sample preparation step that is often time consuming, tedious and frequently overlooked. However, direct online injection methods offer the advantage of reducing sample preparation steps and enabling effective pre-concentration and clean-up of biological fluids. These procedures can be automated and therefore reduce the requirements for handling potentially infectious biomaterial, improve reproducibility, and minimize sample manipulations and potential contamination. This review is focused on the discovery and development of high-performance liquid chromatography (HPLC) and gas chromatography (GC) with different detectors. The drugs covered in this review are antiepileptics, antidepressant (AD), and quinolones. The application of these methods for determination of these drugs in biological, environmental and pharmaceutical samples has also been discussed. PMID:26939618

  17. 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

  18. 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

  19. 78 FR 32669 - New Approaches to Antibacterial Drug Development; Request for Comments

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-31

    ...The Food and Drug Administration's (FDA) Center for Drug Evaluation and Research (CDER) is seeking input from the public on the following topics related to antibacterial drug development: Potential new study designs, proposed priorities for CDER guidances, and strategies intended to slow the rate of emerging resistance to antibacterial drugs. The purpose of this notice is to request......

  20. Undecaprenyl diphosphate synthase inhibitors: antibacterial drug leads.

    PubMed

    Sinko, William; Wang, Yang; Zhu, Wei; Zhang, Yonghui; Feixas, Ferran; Cox, Courtney L; Mitchell, Douglas A; Oldfield, Eric; McCammon, J Andrew

    2014-07-10

    There is a significant need for new antibiotics due to the rise in drug resistance. Drugs such as methicillin and vancomycin target bacterial cell wall biosynthesis, but methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) have now arisen and are of major concern. Inhibitors acting on new targets in cell wall biosynthesis are thus of particular interest since they might also restore sensitivity to existing drugs, and the cis-prenyl transferase undecaprenyl diphosphate synthase (UPPS), essential for lipid I, lipid II, and thus, peptidoglycan biosynthesis, is one such target. We used 12 UPPS crystal structures to validate virtual screening models and then assayed 100 virtual hits (from 450,000 compounds) against UPPS from S. aureus and Escherichia coli. The most promising inhibitors (IC50 ∼2 μM, Ki ∼300 nM) had activity against MRSA, Listeria monocytogenes, Bacillus anthracis, and a vancomycin-resistant Enterococcus sp. with MIC or IC50 values in the 0.25-4 μg/mL range. Moreover, one compound (1), a rhodanine with close structural similarity to the commercial diabetes drug epalrestat, exhibited good activity as well as a fractional inhibitory concentration index (FICI) of 0.1 with methicillin against the community-acquired MRSA USA300 strain, indicating strong synergism. PMID:24827744

  1. 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.

  2. 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.

  3. Antibacterial drug discovery in the 21st century.

    PubMed

    Bush, K

    2004-11-01

    Antibacterial research over the past 50 years has been focused on meeting medical needs caused by infectious, life-threatening pathogens. In spite of the introduction of a variety of antibacterial agents in multiple unrelated drug classes, resistance continues to emerge. The pharmaceutical industry must respond to these clinical challenges by bringing forward a stream of new agents with antibacterial activity against resistant bacteria. Although the projected growth of the anti-infective area may not be as large as for some therapeutic areas, development advantages for these agents include their higher predictability for success, well-defined biomarkers, shorter clinical trials, and shorter duration of therapy leading to fewer long-term safety concerns. Anti-infectives are still attractive commercially, representing the third largest therapeutic area in terms of worldwide sales of 45 bn dollars, with growth predicted at least through 2010, particularly for the hospital-related products. Finally, companies that conduct anti-infective research demonstrate their social responsibility by developing agents to treat patients with acute and potentially fatal illnesses. PMID:15522035

  4. 75 FR 73109 - Guidance for Industry on Antibacterial Drug Products: Use of Noninferiority Trials to Support...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-29

    ... noninferiority (NI) clinical trial designs to evaluate antibacterial drug products. The Agency's thinking in this... clinical trial designs to evaluate antibacterial drug products and to amend ongoing or completed trials accordingly. In the Federal Register of October 15, 2007 (72 FR 58312), FDA announced a notice of...

  5. 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

  6. 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

  7. The future of new oral antibiotics including the quinolones.

    PubMed Central

    Bergeron, M G

    1988-01-01

    It is estimated that more than 110 million dollars' worth of oral antibiotics will have been sold in Canada in 1987. In the next few years several new oral antimicrobial agents will reach the market, including beta-lactamase inhibitors, cephalosporins, monobactams, erythromycins and quinolones. Most of these new agents have a broader spectrum of antibacterial activity than the presently available oral antibiotics. A few have a longer half-life and can be administered once a day. The new oral drugs, especially the quinolones and possibly beta-lactams, will now be used to treat infections that in the past could be treated only parenterally. Exacerbations of pulmonary infections due to Pseudomonas aeruginosa in cystic fibrosis can now be successfully treated at home with the new quinolones. Osteomyelitis, arthritis, pneumonia and pyelonephritis will most likely be treated at home in the future. In severe infections patients will be admitted to hospital for short courses of parenteral therapy, followed by oral treatment. If used appropriately the new oral agents may lead to new approaches to the treatment of infectious diseases. PMID:3275479

  8. 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... workshop regarding the design of Clinical Trials for Systemic Antibacterial Agents for the Treatment of... of clinical trials of antibacterial agents for the treatment of acute otitis media (middle...

  9. 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...

  10. 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...

  11. 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...

  12. 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...

  13. 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...

  14. Legionella pneumophila Carbonic Anhydrases: Underexplored Antibacterial Drug Targets

    PubMed Central

    Supuran, Claudiu T.

    2016-01-01

    Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes which catalyze the hydration of carbon dioxide to bicarbonate and protons. Many pathogenic bacteria encode such enzymes belonging to the α-, β-, and/or γ-CA families. In the last decade, enzymes from some of these pathogens, including Legionella pneumophila, have been cloned and characterized in detail. These enzymes were shown to be efficient catalysts for CO2 hydration, with kcat values in the range of (3.4–8.3) × 105 s−1 and kcat/KM values of (4.7–8.5) × 107 M−1·s−1. In vitro inhibition studies with various classes of inhibitors, such as anions, sulfonamides and sulfamates, were also reported for the two β-CAs from this pathogen, LpCA1 and LpCA2. Inorganic anions were millimolar inhibitors, whereas diethyldithiocarbamate, sulfamate, sulfamide, phenylboronic acid, and phenylarsonic acid were micromolar ones. The best LpCA1 inhibitors were aminobenzolamide and structurally similar sulfonylated aromatic sulfonamides, as well as acetazolamide and ethoxzolamide (KIs in the range of 40.3–90.5 nM). The best LpCA2 inhibitors belonged to the same class of sulfonylated sulfonamides, together with acetazolamide, methazolamide, and dichlorophenamide (KIs in the range of 25.2–88.5 nM). Considering such preliminary results, the two bacterial CAs from this pathogen represent promising yet underexplored targets for obtaining antibacterials devoid of the resistance problems common to most of the clinically used antibiotics, but further studies are needed to validate them in vivo as drug targets. PMID:27322334

  15. Legionella pneumophila Carbonic Anhydrases: Underexplored Antibacterial Drug Targets.

    PubMed

    Supuran, Claudiu T

    2016-01-01

    Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes which catalyze the hydration of carbon dioxide to bicarbonate and protons. Many pathogenic bacteria encode such enzymes belonging to the α-, β-, and/or γ-CA families. In the last decade, enzymes from some of these pathogens, including Legionella pneumophila, have been cloned and characterized in detail. These enzymes were shown to be efficient catalysts for CO₂ hydration, with kcat values in the range of (3.4-8.3) × 10⁵ s(-1) and kcat/KM values of (4.7-8.5) × 10⁷ M(-1)·s(-1). In vitro inhibition studies with various classes of inhibitors, such as anions, sulfonamides and sulfamates, were also reported for the two β-CAs from this pathogen, LpCA1 and LpCA2. Inorganic anions were millimolar inhibitors, whereas diethyldithiocarbamate, sulfamate, sulfamide, phenylboronic acid, and phenylarsonic acid were micromolar ones. The best LpCA1 inhibitors were aminobenzolamide and structurally similar sulfonylated aromatic sulfonamides, as well as acetazolamide and ethoxzolamide (KIs in the range of 40.3-90.5 nM). The best LpCA2 inhibitors belonged to the same class of sulfonylated sulfonamides, together with acetazolamide, methazolamide, and dichlorophenamide (KIs in the range of 25.2-88.5 nM). Considering such preliminary results, the two bacterial CAs from this pathogen represent promising yet underexplored targets for obtaining antibacterials devoid of the resistance problems common to most of the clinically used antibiotics, but further studies are needed to validate them in vivo as drug targets. PMID:27322334

  16. 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

  17. Electrospinning polyvinylidene fluoride fibrous membranes containing anti-bacterial drugs used as wound dressing.

    PubMed

    He, Ting; Wang, Jingnan; Huang, Peilin; Zeng, Baozhen; Li, Haihong; Cao, Qingyun; Zhang, Shiying; Luo, Zhuo; Deng, David Y B; Zhang, Hongwu; Zhou, Wuyi

    2015-06-01

    The aim of this study was to synthesis drug-loaded fibrous membrane scaffolds for potential applications as wound dressing. Polyvinylidene fluoride (PVDF) fibrous membranes were loaded with enrofloxacin (Enro) drugs by using an electrospinning process, and their mechanical strength, drug release profile and anti-bacterial properties were evaluated. Enro drug-loaded PVDF membranes exhibited good elasticity, flexibility and excellent mechanical strength. The electrospinning Enro/PVDF membranes showed a burst drug release in the initial 12h, followed by sustained release for the next 3 days, which was an essential property for antibiotic drugs applied for wound healing. The drug-loaded PVDF fibrous membranes displayed excellent anti-bacterial activity toward Escherichia coli and Staphylococcus aureus. The results suggest that electrospinning PVDF membrane scaffolds loaded with drugs can be used as wound dressing. PMID:25936562

  18. Update on Quinolone Resistance in Neisseria gonorrhoeae.

    PubMed

    Zenilman, Jonathan M.

    2002-04-01

    Quinolones are widely used for treating gonococcal infections, typically in single-dose, oral regimens. However, in the 1990s, quinolone-resistant Neisseria gonorrhoeae emerged, potentially compromising the utility of this drug class. In the past year, these strains have widely disseminated, accounting for over half of isolates in parts of Southeast Asia. The molecular mechanism of resistance has been localized to multiple mutations in genes coding for the bacterial DNA gyrase and topoisomerase enzymes. These mutations accumulate until the minimum inhibitory concentration is 4.0 g/mL or more, which in clinical studies appears to be the threshold for clinical treatment failure. Quinolone-resistant N. gonorrhoeae is independent from other plasmid- and chromosomally-mediated resistance determinants; nearly all isolates to date have been sensitive to cephalosporins and spectinomycin. Nevertheless, designing public health strategies to contain quinolone-resistant N. gonorrhoeae will be difficult. PMID:11927047

  19. 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

  20. [Classification and prevalence of plasmid-mediated quinolone resistance qnr genes in China--A review].

    PubMed

    Yan, Lei; Xu, Hai

    2016-02-01

    Quinolone antibacterial drugs, developing from the treatment of urinary tract infection in early time and now from the treatment of intestinal infection and respiratory infection, have been widely used in clinical, animal husbandry and aquaculture. Bacteria gradually become resistant to them and resistance mechanism is more and more complicated. Quinolone resistance mechanism is mainly divided into chromosome mediated resistance and plasmid mediated resistance, the latter plays an important role in spreading of antibiotic resistance. In 1998, plasmid mediated quinolone resistance mechanism was reported for the first time, namely the qnr gene mediated fluoroquinolone resistance mechanism. qnr genes can spread rapidly in different bacteria, which causes the infection difficult to control, makes the nosocomial infection popular in a wide range. In addition, qnr genes are usually associated with β-lactamase resistance gene. They exist in complex integron and integrate with the other varieties of resistance genes, which narrows the space of clinical medicine choose or drug combinations use to treat related bacterial infection and brings us a serious challenge. In this review, we provide a detailed overview for the historical discovery, classification, the resistance mechanisms of qnr genes, and the prevalence of those genes in China. PMID:27373065

  1. 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.

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

    PubMed

    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 (O2.-) dismutation was assayed by their ability to inhibit the reduction of nitroblue tetrazolium (NBT). PMID:21212015

  3. 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).

  4. 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

  5. In vivo and in vitro toxicodynamic analyses of new quinolone-and nonsteroidal anti-inflammatory drug-induced effects on the central nervous system.

    PubMed

    Kita, H; Matsuo, H; Takanaga, H; Kawakami, J; Yamamoto, K; Iga, T; Naito, M; Tsuruo, T; Asanuma, A; Yanagisawa, K; Sawada, Y

    1999-05-01

    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 gamma-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 microM) > FRP (0. 3 microM) > FLB (0.2 microM). 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

  6. Single-step extraction followed by LC for determination of (fluoro)quinolone drug residues in muscle, eggs, and milk.

    PubMed

    Cho, Hee-Jung; Yi, Hee; Cho, Soo Min; Lee, Dong Goo; Cho, Kyul; Abd el-Aty, A M; Shim, Jae-Han; Lee, Soon-Ho; Jeong, Ji-Yoon; Shin, Ho-Chul

    2010-04-01

    In this study, a simplified method for the extraction and determination of seven fluoroquinolone residues (danofloxacin, difloxacin, enrofloxacin, marbofloxacin, orbifloxacin, ofloxacin, and sarafloxacin) and three quinolones (oxolinic acid, flumequine, and nalidixic acid), in porcine muscle, table eggs, and commercial whole milk, which required no cleanup step, was devised. This procedure involves the extraction of analytes from the samples via liquid-phase extraction, and the subsequent quantitative determination was accomplished via LC-fluorescence detection. Analyte separation was successfully conducted on an XBridge-C(18) column, with a linear gradient mobile phase composed of acetonitrile and 0.01 M oxalic acid buffer at pH=3.5. The one-step liquid-liquid extraction method evidenced good selectivity, precision (RSDs=0.26-15.07%), and recovery of the extractable analytes, ranging from 61.12 to 115.93% in matrices. The LOQs ranged from 0.3 to 25 microg/kg. A survey of ten samples purchased from local markets was conducted, and none of the samples harbored fluoroquinolone residues. This method is an improvement over existing methodologies, since no additional cleanup was necessary. PMID:20175091

  7. Antibacterial Activities and Antibacterial Mechanism of Polygonum cuspidatum Extracts against Nosocomial Drug-Resistant Pathogens.

    PubMed

    Su, Pai-Wei; Yang, Cheng-Hong; Yang, Jyh-Ferng; Su, Pei-Yu; Chuang, Li-Yeh

    2015-01-01

    Recently, drug resistance due to the extensive abuse and over-use of antibiotics has become an increasingly serious problem, making the development of alternative antibiotics a very urgent issue. In this study, the Chinese herbal medicine, Polygonum cuspidatum, was extracted with 95% ethanol and the crude extracts were further purified by partition based on solvent polarity. The antimicrobial activities of the extracts and fractions were determined by the disk diffusion and minimum inhibitory concentration (MIC) methods. The results showed that the ethyl ether fraction (EE) of the ethanol extracts possesses a broader antimicrobial spectrum and greater antimicrobial activity against all of the tested clinical drug-resistant isolates, with a range of MIC values between 0.1-3.5 mg/mL. The active extract showed complete inhibition of pathogen growth and did not induce resistance to the active components. In addition, according to scanning electron microscope observations, EE resulted in greater cell morphological changes by degrading and disrupting the cell wall and cytoplasmic membrane, whereby ultimately this cell membrane integrity damage led to cell death. In conclusion, the EE extracts from Polygonum cuspidatum may provide a promising antimicrobial agent for therapeutic applications against nosocomial drug-resistant bacteria. PMID:26087259

  8. 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.

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. Nanomechanics of drug-target interactions and antibacterial resistance detection.

    PubMed

    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 specificity. 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 structures. We developed a new model(1) 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

  17. 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

  18. 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

  19. 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

  20. Peptide deformylase: a new target in antibacterial, antimalarial and anticancer drug discovery.

    PubMed

    Sangshetti, Jaiprakash N; Khan, Firoz A Kalam; Shinde, Devanand B

    2015-01-01

    Peptide deformylase (PDF) is a class of metalloenzyme responsible for catalyzing the removal of the N-formyl group from N-terminal methionine following translation. PDF inhibitors are moving into new phase of drug development. Initially, PDF was considered as an important target in antibacterial drug discovery; however genome database searches have revealed PDF-like sequences in parasites (P. falciparum) and human, widening the utility of this target in antimalarial and anticancer drug discovery along with antibacterial. Using structural and mechanistic information together with high throughput screening, several types of chemical classes of PDF inhibitors with improved efficacy and specificity have been identified. Various drugs like, GSK-1322322 (Phase II), BB-83698 (Phase I), and LBM-415 (Phase I) have entered into clinical developments. Developments in the field have prompted us to review the current aspects of PDFs, especially their structures, different classes of PDF inhibitors, and molecular modeling studies. In nut shell, this review enlightens PDF as a versatile target along with its inhibitors and future perspectives of different PDF inhibitors. PMID:25174923

  1. Possible intermolecular interaction between quinolones and biphenylacetic acid inhibits gamma-aminobutyric acid receptor sites.

    PubMed

    Akahane, K; Kimura, Y; Tsutomi, Y; Hayakawa, I

    1994-10-01

    The combination of some new quinolone antibacterial agents with 4-biphenylacetic acid (BPAA), a metabolite of fenbufen, is known to specifically induce functional blockade of the gamma-aminobutyric acid (GABA) receptors. The mechanisms of these drug interactions were further examined. Scatchard analysis of [3H]muscimol binding to rat brain plasma membranes in the presence of enoxacin and BPAA revealed that a significant decrease in the number of muscimol binding sites was produced without affecting the affinity of binding to the receptors. In the presence of norfloxacin, BPAA inhibited muscimol binding the most potently of the six BPAA-related compounds tested. Fenbufen and 9,10-dihydro-gamma-oxo-2-phenanthrenebutyric acid also inhibited the binding, and 4-biphenylcarboxylic acid and methyl 4-biphenylacetate inhibited it slightly, but 3-benzoylpropionic acid exhibited no competitive inhibition. Accordingly, hybrid molecules of norfloxacin and BPAA were synthesized for stereochemical analysis of these drug interactions. A hybrid with a -CONH(CH2)3- chain between norfloxacin and BPAA (flexible structure) inhibited muscimol binding, and intracisternal injection of this hybrid caused clonic convulsions in mice more potently than the combination of norfloxacin and BPAA did. In contrast, a hybrid linked by -CONH- (stretched structure) showed almost no such inhibitory effect. 1H NMR analysis indicated the presence of intramolecular attraction at the quinoline ring of the hybrid exhibiting the antagonistic activity. These results suggest the possibility that quinolones and BPAA interact with the GABA receptor at nearby sites and that the binding affinity of quinolones to the GABA receptors is largely enhanced by the intermolecular interaction with BPAA. PMID:7840564

  2. Possible intermolecular interaction between quinolones and biphenylacetic acid inhibits gamma-aminobutyric acid receptor sites.

    PubMed Central

    Akahane, K; Kimura, Y; Tsutomi, Y; Hayakawa, I

    1994-01-01

    The combination of some new quinolone antibacterial agents with 4-biphenylacetic acid (BPAA), a metabolite of fenbufen, is known to specifically induce functional blockade of the gamma-aminobutyric acid (GABA) receptors. The mechanisms of these drug interactions were further examined. Scatchard analysis of [3H]muscimol binding to rat brain plasma membranes in the presence of enoxacin and BPAA revealed that a significant decrease in the number of muscimol binding sites was produced without affecting the affinity of binding to the receptors. In the presence of norfloxacin, BPAA inhibited muscimol binding the most potently of the six BPAA-related compounds tested. Fenbufen and 9,10-dihydro-gamma-oxo-2-phenanthrenebutyric acid also inhibited the binding, and 4-biphenylcarboxylic acid and methyl 4-biphenylacetate inhibited it slightly, but 3-benzoylpropionic acid exhibited no competitive inhibition. Accordingly, hybrid molecules of norfloxacin and BPAA were synthesized for stereochemical analysis of these drug interactions. A hybrid with a -CONH(CH2)3- chain between norfloxacin and BPAA (flexible structure) inhibited muscimol binding, and intracisternal injection of this hybrid caused clonic convulsions in mice more potently than the combination of norfloxacin and BPAA did. In contrast, a hybrid linked by -CONH- (stretched structure) showed almost no such inhibitory effect. 1H NMR analysis indicated the presence of intramolecular attraction at the quinoline ring of the hybrid exhibiting the antagonistic activity. These results suggest the possibility that quinolones and BPAA interact with the GABA receptor at nearby sites and that the binding affinity of quinolones to the GABA receptors is largely enhanced by the intermolecular interaction with BPAA. PMID:7840564

  3. Fate and antibacterial potency of anticoccidial drugs and their main abiotic degradation products.

    PubMed

    Hansen, Martin; Krogh, Kristine A; Brandt, Asbjørn; Christensen, Jan H; Halling-Sørensen, Bent

    2009-02-01

    The antibacterial potency of eight anticoccidial drugs was tested in a soil bacteria bioassay (pour plate method), EC(50)-values between 2.4 and 19.6 microM were obtained; however, one compound, nicarbazin exhibited an EC(50)-value above the maximum tested concentration (21 microM, 9.1 mg L(-1)). The potency of mixtures of two of the compounds, narasin and nicarbazin, was synergistic (more than additive) with 10-fold greater antibacterial potency of the mixture than can be explained by their individual EC(50)-values. The influence of pH, temperature, oxygen concentration and light on the transformation of robenidine and salinomycin was investigated. Robenidine was transformed by photolysis (DT(50) of 4.1 days) and was unstable at low pH (DT(50) of approximately 4 days); salinomycin was merely transformed at low pH, the latter into an unknown number of products. The antibacterial potency of the mixtures of transformation products of robenidine after photolysis and at low pH was comparable with that of the parent compound. Finally five photo-transformation products of robenidine were structural elucidated by accurate mass measurements, i-FIT values (isotopic pattern fit) and MS/MS fragmentation patterns. PMID:18976841

  4. 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

    ... clinical trial design and the types of infectious disease indications for which the NI clinical trial... 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...

  5. Ligand and Structure-Based Approaches for the Identification of Peptide Deformylase Inhibitors as Antibacterial Drugs

    PubMed Central

    Gao, Jian; Liang, Li; Zhu, Yasheng; Qiu, Shengzhi; Wang, Tao; Zhang, Ling

    2016-01-01

    Peptide deformylase (PDF) is a metalloprotease catalyzing the removal of a formyl group from newly synthesized proteins, which makes it an important antibacterial drug target. Given the importance of PDF inhibitors like actinonin in antibacterial drug discovery, several reported potent PDF inhibitors were used to develop pharmacophore models using the Galahad module of Sybyl 7.1 software. Generated pharmacophore models were composed of two donor atom centers, four acceptor atom centers and two hydrophobic groups. Model-1 was screened against the Zinc database and several compounds were retrieved as hits. Compounds with Qfit values of more than 60 were employed to perform a molecular docking study with the receptor Escherichia coli PDF, then compounds with docking score values of more than 6 were used to predict the in silico pharmacokinetic and toxicity risk via OSIRIS property explorer. Two known PDF inhibitors were also used to perform a molecular docking study with E. coli PDF as reference molecules. The results of the molecular docking study were validated by reproducing the crystal structure of actinonin. Molecular docking and in silico pharmacokinetic and toxicity prediction studies suggested that ZINC08740166 has a relatively high docking score of 7.44 and a drug score of 0.78. PMID:27428963

  6. Ligand and Structure-Based Approaches for the Identification of Peptide Deformylase Inhibitors as Antibacterial Drugs.

    PubMed

    Gao, Jian; Liang, Li; Zhu, Yasheng; Qiu, Shengzhi; Wang, Tao; Zhang, Ling

    2016-01-01

    Peptide deformylase (PDF) is a metalloprotease catalyzing the removal of a formyl group from newly synthesized proteins, which makes it an important antibacterial drug target. Given the importance of PDF inhibitors like actinonin in antibacterial drug discovery, several reported potent PDF inhibitors were used to develop pharmacophore models using the Galahad module of Sybyl 7.1 software. Generated pharmacophore models were composed of two donor atom centers, four acceptor atom centers and two hydrophobic groups. Model-1 was screened against the Zinc database and several compounds were retrieved as hits. Compounds with Qfit values of more than 60 were employed to perform a molecular docking study with the receptor Escherichia coli PDF, then compounds with docking score values of more than 6 were used to predict the in silico pharmacokinetic and toxicity risk via OSIRIS property explorer. Two known PDF inhibitors were also used to perform a molecular docking study with E. coli PDF as reference molecules. The results of the molecular docking study were validated by reproducing the crystal structure of actinonin. Molecular docking and in silico pharmacokinetic and toxicity prediction studies suggested that ZINC08740166 has a relatively high docking score of 7.44 and a drug score of 0.78. PMID:27428963

  7. Quinolone-based HDAC inhibitors.

    PubMed

    Balasubramanian, Gopalan; Kilambi, Narasimhan; Rathinasamy, Suresh; Rajendran, Praveen; Narayanan, Shridhar; Rajagopal, Sridharan

    2014-08-01

    HDAC inhibitors emerged as promising drug candidates in combating wide variety of cancers. At present, two of the compounds SAHA and Romidepsin were approved by FDA for cutaneous T-cell lymphoma and many are in various clinical phases. A new quinolone cap structure was explored with hydroxamic acid as zinc-binding group (ZBG). The pan HDAC inhibitory and antiproliferative activities against three human cancer cell lines HCT-116 (colon), NCI-H460 (lung) and U251 (glioblastoma) of the compounds (4a-4w) were evaluated. Introduction of heterocyclic amines in CAP region increased the enzyme inhibitory and antiproliferative activities and few of the compounds tested are metabolically stable in both MLM and HLM. PMID:25019596

  8. 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

  9. Distinct effects of the UvrD helicase on topoisomerase-quinolone-DNA ternary complexes.

    PubMed

    Shea, M E; Hiasa, H

    2000-05-12

    Quinolone antibacterial drugs target both DNA gyrase (Gyr) and topoisomerase IV (Topo IV) and form topoisomerase-quinolone-DNA ternary complexes. The formation of ternary complexes results in the inhibition of DNA replication and leads to the generation of double-strand breaks and subsequent cell death. Here, we have studied the consequences of collisions between the UvrD helicase and the ternary complexes formed with either Gyr, Topo IV, or a mutant Gyr, Gyr (A59), which does not wrap the DNA strand around itself. We show (i) that Gyr-norfloxacin (Norf)-DNA and Topo IV-Norf-DNA, but not Gyr (A59)-Norf-DNA, ternary complexes inhibit the UvrD-catalyzed strand-displacement activity, (ii) that a single-strand break is generated at small portions of the ternary complexes upon their collisions with UvrD, and (iii) that the majority of Topo IV-Norf-DNA ternary complexes become nonreversible when UvrD collides with the Topo IV-Norf-DNA ternary complexes, whereas the majority of Gyr-Norf-DNA ternary complexes remain reversible after their collision with the UvrD helicase. These results indicated that different DNA repair mechanisms might be involved in the repair of Gyr-Norf-DNA and Topo IV-Norf-DNA ternary complexes. PMID:10799552

  10. In vitro activity of sparfloxacin compared with those of five other quinolones.

    PubMed

    Cantón, E; Pemán, J; Jimenez, M T; Ramón, M S; Gobernado, M

    1992-03-01

    The in vitro activity of sparfloxacin, a new difluorinated quinolone, was evaluated against 857 gram-positive and gram-negative clinical isolates and compared with those of ciprofloxacin, norfloxacin, ofloxacin, fleroxacin, and lomefloxacin. The MIC of sparfloxacin for 90% of the members of the family Enterobacteriaceae tested was 0.5 microgram/ml (range, 0.06 to 4.0 micrograms/ml); only for members of the genera Serratia, Citrobacter, and Providencia were MICs above 1 microgram/ml. Some 90% of Pseudomonas aeruginosa isolates were inhibited by 8 micrograms of the drug per ml. The MICs for 90% of Staphylococcus spp. and Enterococcus faecalis were 0.12 and 2 micrograms/ml, respectively. All (100%) Streptococcus pneumoniae strains were inhibited by 0.5 microgram/ml. The inoculum size had little effect on either the MIC or the MBC of sparfloxacin. An increase in the magnesium concentration from 1.1 to 8.4 mM increased the MIC between 2 and 10 times, depending on the genus tested. Sparfloxacin was less active at pH 5. The antibacterial activity of sparfloxacin against gram-positive bacteria was generally higher than those of the quinolones with which it was compared; against Streptococcus pneumoniae, sparfloxacin was four- and eightfold more active than ofloxacin and ciprofloxacin, respectively. The activity of sparfloxacin against gram-negative rods was generally comparable to that of ciprofloxacin except against Enterobacter and Acinetobacter spp., Pseudomonas cepacia, Xanthomonas maltophilia, and Alcaligenes and Flavobacterium spp., against which sparfloxacin was the most active quinolone. PMID:1320362

  11. 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

  12. Inactivation of indispensable bacterial proteins by early proteins of bacteriophages: implication in antibacterial drug discovery.

    PubMed

    Sau, S; Chattoraj, P; Ganguly, T; Chanda, P K; Mandal, N C

    2008-06-01

    Bacteriophages utilize host bacterial cellular machineries for their own reproduction and completion of life cycles. The early proteins that phage synthesize immediately after the entry of their genomes into bacterial cells participate in inhibiting host macromolecular biosynthesis, initiating phage-specific replication and synthesizing late proteins. Inhibition of synthesis of host macromolecules that eventually leads to cell death is generally performed by the physical and/or chemical modification of indispensable host proteins by early proteins. Interestingly, most modified bacterial proteins were shown to take part actively in phage-specific transcription and replication. Research on phages in last nine decades has demonstrated such lethal early proteins that interact with or chemically modify indispensable host proteins. Among the host proteins inhibited by lethal phage proteins, several are not inhibited by any chemical inhibitor available today. Under the context of widespread dissemination of antibiotic-resistant strains of pathogenic bacteria in recent years, the information of lethal phage proteins and cognate host proteins could be extremely invaluable as they may lead to the identification of novel antibacterial compounds. In this review, we summarize the current knowledge about some early phage proteins, their cognate host proteins and their mechanism of action and also describe how the above interacting proteins had been exploited in antibacterial drug discovery. PMID:18537683

  13. Advanced biopolymer-coated drug-releasing titania nanotubes (TNTs) implants with simultaneously enhanced osteoblast adhesion and antibacterial properties.

    PubMed

    Kumeria, Tushar; Mon, Htwe; Aw, Moom Sinn; Gulati, Karan; Santos, Abel; Griesser, Hans J; Losic, Dusan

    2015-06-01

    Here, we report on the development of advanced biopolymer-coated drug-releasing implants based on titanium (Ti) featuring titania nanotubes (TNTs) on its surface. These TNT arrays were fabricated on the Ti surface by electrochemical anodization, followed by the loading and release of a model antibiotic drug, gentamicin. The osteoblastic adhesion and antibacterial properties of these TNT-Ti samples are significantly improved by loading antibacterial payloads inside the nanotubes and modifying their surface with two biopolymer coatings (PLGA and chitosan). The improved osteoblast adhesion and antibacterial properties of these drug-releasing TNT-Ti samples are confirmed by the adhesion and proliferation studies of osteoblasts and model Gram-positive bacteria (Staphylococcus epidermidis). The adhesion of these cells on TNT-Ti samples is monitored by fluorescence and scanning electron microscopies. Results reveal the ability of these biopolymer-coated drug-releasing TNT-Ti substrates to promote osteoblast adhesion and proliferation, while effectively preventing bacterial colonization by impeding their proliferation and biofilm formation. The proposed approach could overcome inherent problems associated with bacterial infections on Ti-based implants, simultaneously enabling the development of orthopedic implants with enhanced and synergistic antibacterial functionalities and bone cell promotion. PMID:25944564

  14. 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

  15. [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

  16. Photoprocesses in quinolone substituted

    NASA Astrophysics Data System (ADS)

    Vasilyeva, N. Y.; Vusovich, O. V.

    2002-03-01

    In the present work the analysis of the possible ways of energy degradation of electron excited states of 4-methyl-7- hydxyquinolone-2 (Q) and its protolytic species is presented (Figure 1); a ratio of radiative and nonradiative channels of deactivation of energy of electronic excitation is established; constants of photophysical processes (internal and intercrossing conversion), proceeding after act of absorption of light are designed. Study of exited state intramolecular proton transfer (ESIPT) in quinolones is interesting as a source of information on the relative importance of these processes in the photophysics and photochemistry of such molecular systems.

  17. 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

  18. Chemical structure and pharmacokinetics of novel quinolone agents represented by avarofloxacin, delafloxacin, finafloxacin, zabofloxacin and nemonoxacin.

    PubMed

    Kocsis, Bela; Domokos, J; Szabo, D

    2016-01-01

    Quinolones are potent antimicrobial agents with a basic chemical structure of bicyclic ring. Fluorine atom at position C-6 and various substitutions on the basic quinolone structure yielded fluoroquinolones, namely norfloxacin, ciprofloxacin, levofloxacin, moxifloxacin and numerous other agents. The target molecules of quinolones and fluoroquinolones are bacterial gyrase and topoisomerase IV enzymes. Broad-spectrum and excellent tissue penetration make fluoroquinolones potent agents but their toxic side effects and increasing number of resistant pathogens set limits on their use. This review focuses on recent advances concerning quinolones and fluoroquinolones, we will be summarising chemical structure, mode of action, pharmacokinetic properties and toxicity. We will be describing fluoroquinolones introduced in clinical trials, namely avarofloxacin, delafloxacin, finafloxacin, zabofloxacin and non-fluorinated nemonoxacin. These agents have been proved to have enhanced antibacterial effect even against ciprofloxacin resistant pathogens, and found to be well tolerated in both oral and parenteral administrations. These features are going to make them potential antimicrobial agents in the future. PMID:27215369

  19. 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

  20. 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

  1. 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.

  2. 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

  3. 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

  4. New antibacterial, non-genotoxic materials, derived from the functionalization of the anti-thyroid drug methimazole with silver ions.

    PubMed

    Sainis, I; Banti, C N; Owczarzak, A M; Kyros, L; Kourkoumelis, N; Kubicki, M; Hadjikakou, S K

    2016-07-01

    The new silver(I) compound {[AgBr(μ2-S-MMI)(TPP))]2} (1) and the known one [AgCl(TPP)2(MMI)] (2) were obtained by refluxing toluene solutions of silver(I) halide with triphenylphosphine (TPP) and the anti-thyroid drug 2-mercapto-1-methyl-imidazole or methimazole (MMI). The complexes were characterized by m.p., vibrational spectroscopy (mid-FT-IR), (1)H, (31)P-NMR, UV-Vis spectroscopic techniques and X-ray crystallography. The antibacterial effect of 1 and 2 against the bacterial species Pseudomonas aeruginosa (PAO) and Escherichia coli was evaluated. Compound 1 exhibits comparable activity to the corresponding one of the silver nitrate which is an antibacterial drug in use. The in vivo genotoxicity of 1-2 by the mean of Allium cepa test shows no alterations in the mitotic index values due to the absence of chromosomal aberrations. The mechanism of action of the title compounds is evaluated. The DNA binding tests indicate the ability of the complexes 1-2 to modify the activity of the bacteria. The binding constants of 1-2 towards CT-DNA indicate interaction through opening of the hydrogen bonds of DNA. Docking studies on DNA-complexes interactions confirm the binding of both complexes 1-2 in the major groove of the CT-DNA. In conclusion the silver complex 1 is an anti-bacterial and non-genotoxic material, which can be applied to antibacterial drug in the future. PMID:26765999

  5. Advancing New Antibacterial Drug Development for Treatment of Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia.

    PubMed

    Toerner, Joseph G; Rubin, Daniel

    2016-08-15

    The Clinical Trials Transformation Initiative (CTTI), a public-private partnership comprised of representatives from academia, the pharmaceutical industry, and the federal government including the US Food and Drug Administration, formed a group working toward a common goal of intensified research to facilitate the development of new antibacterial drug therapies for treatment of hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP). The summary of the CTTI HABP/VABP project in this supplement of Clinical Infectious Diseases is a first step in this direction. PMID:27481951

  6. Study of fluorescence characteristics of the charge-transfer reaction of quinolone agents with bromanil

    NASA Astrophysics Data System (ADS)

    Li, Wen-Ying; Chen, Xiao-Fang; Xuan, Chun-Sheng

    2009-01-01

    A spectrofluorimetric method was discussed for the determination of three antibacterial quinolone derivatives, ofloxacin (OFL), norfloxacin (NOR) and ciprofloxacin (CIP) through charge-transfer complexation (CTC) with 2,3,5,6-tetrabromo-1,4-benzoquinone (bromanil, TBBQ). The method was based on the reaction of these drugs as n-electron donors with the π-acceptor TBBQ. TBBQ was found to react with these drugs to produce a kind of yellow complexes and the fluorescence intensities of the complexes were enhanced by 29-36 times more than those of the corresponding monomers. UV-vis, 1H NMR and XPS techniques were used to study the complexes formed. The various experimental parameters affecting the fluorescence intensity were studied and optimized. Under optimal reaction conditions, the rectilinear calibration graphs were obtained in the concentration range of 0.021-2.42 μg mL -1, 0.017-2.63 μg mL -1 and 0.019-2.14 μg mL -1 for OFL, NOR and CIP, respectively. The methods developed were applied successfully to the determination of the subject drugs in their pharmaceutical dosage forms with good precision and accuracy compared to official and reported methods as revealed by t- and F-tests.

  7. 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

  8. Synthesis, antibacterial activity, and biological evaluation of formyl hydroxyamino derivatives as novel potent peptide deformylase inhibitors against drug-resistant bacteria.

    PubMed

    Yang, Shouning; Shi, Wei; Xing, Dong; Zhao, Zheng; Lv, Fengping; Yang, Liping; Yang, Yushe; Hu, Wenhao

    2014-10-30

    Peptide deformylase (PDF) has been identified as a promising target for novel antibacterial agents. In this study, a series of novel formyl hydroxyamino derivatives were designed and synthesized as PDF inhibitors and their antibacterial activities were evaluated. Among the potent PDF inhibitors (1o, 1q, 1o', 1q', and 1x), in vivo studies showed that compound 1q possesses mild toxicity, a good pharmacokinetic profile and protective effects. The good in vivo efficacy and low toxicity suggest that this class of compounds has potential for development and use in future antibacterial drugs. PMID:25151577

  9. LD50 value, phototoxicity and convulsion induction test of the new quinolone antibacterial agent (S)-10-[(S)-(8-amino-6-azaspiro[3,4]octan-6-yl)]-9-fluoro-2, 3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxyl ic acid hemihydrate in laboratory animals.

    PubMed

    Shimoda, K; Akahane, K; Nomura, M; Kato, M

    1996-06-01

    (S)-10-[(S)-(8-Amino-6-azaspiro[3,4]octan-6-yl)]-9-fluoro-2, 3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxyli c acid hemihydrate (CAS 151390-79-3, DV-7751a) a new quinolone antibacterial agent, was examined for LD50 value, phototoxicity and convulsion inducing potential in laboratory animals. A single oral administration of DV-7751a induced soft stool in rats at 1000 and 2000 mg/ kg and in monkeys at 250 mg/kg and vomiting in monkeys at 500 mg/kg or more. A single intravenous administration caused a decrease in locomotor activity, respiratory depression, convulsion, pulmonary edema and death in rats and mice. The LD50 values with oral administration were more than 2000 mg/ kg for rats and mice and more than 250 mg/kg for monkeys, and those with intravenous administration were 164.3 mg/kg for rats of both sexes at an injection rate of 2 ml/min, 118.8 mg/kg for male rats and 104 to 125 mg/kg for female rats at 0.5 ml/min, and 184.7 mg/kg for male mice and 187.4 mg/kg for female mice. DV-7751a showed very weak phototoxicity in mice after single oral administration of 600 mg/kg, followed by UVA irradiation, but no convulsion after oral administration of 200 or 1000 mg/kg in combination with 4-biphenylacetic acid at 400 mg/kg. PMID:8767355

  10. 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

  11. Studies of the photooxidant properties of antibacterial fluoroquinolones and their naphthalene derivatives.

    PubMed

    Vargas, F; Zoltan, T; Ramirez, A H; Cordero, T; Chavez, V; Izzo, C; López, V; Cárdenas, Y M; Fernández, A; Hincapie, L; Fuentes, A

    2009-02-01

    We synthesized and determined the production of reactive oxygen species (ROS) as 1O2, *-O2, *OH, H2O2 during the photolysis with UV-A light of three antibacterial quinolones and their naphthyl ester derivatives. Singlet oxygen and ROS dose-dependant generation from norfloxacin (1), enoxacin (2), ciprofloxacin (3) and their respective naphthyl ester derivatives 4-6 were detecting in cell-free systems by the histidine assay and by luminol-enhanced chemiluminescence (LCL). Both the electronic absorption and emission spectra were quantified and their photostability determined. The antibacterial activity in darkness and under irradiation of compounds 4, 5 and 6 was tested on E. coli and compared with their parent drugs. PMID:19320285

  12. Recurrent mania consequent to quinolones exposure: A case report and review of literature.

    PubMed

    Sahoo, Swapnajeet; Aneja, Jitender; Basu, Debasish

    2016-01-01

    Antibiotics are the one of the most commonly used group, of drugs, in general medical and surgical practice. The quinolone antibiotics can lead to a range of adverse neuropsychiatric effects with most of the reports due to ciprofloxacin and ofloxacin. Here, we report an interesting and rarely described psychiatric manifestation of recurrent mania following the use of quinolone antibiotics, and briefly review the available literature. PMID:27453864

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  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. 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

  20. 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

  1. 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

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

    PubMed Central

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

    2013-01-01

    In vitro activity of ozenoxacin, a novel nonfluorinated topical (L. D. Saravolatz and J. Leggett, Clin. Infect. Dis. 37:1210–1215, 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

  3. 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

  4. Routes of quinolone permeation in Escherichia coli.

    PubMed Central

    Chapman, J S; Georgopapadakou, N H

    1988-01-01

    The uptake of quinolone antibiotics by Escherichia coli was investigated by using fleroxacin (RO 23-6240, AM 833) as a prototype compound. The uptake of fleroxacin was reduced and its MIC was increased in the presence of magnesium. Quinolones induced lipopolysaccharide release, increased cell-surface hydrophobicity and outer membrane permeability to B-lactams, and sensitized cells to lysis by detergents. These effects were also antagonized by magnesium and were very similar to those seen with EDTA and gentamicin. MICs of quinolones in portin-deficient strains were increased relative to those of the parent strain, consistent with a porin pathway of entry. However, MICs were further increased in the presence of magnesium; the size of the additional increase showed a positive correlation with quinolone hydrophobicity in an OmpF- OmpC- OmpA- strain. When quinolones were mixed with divalent cations in solution, changes in quinolone fluorescence suggestive of metal chelation were observed. The addition of fleroxacin to a cell suspension resulted in a rapid initial association of fluorescence with cells, followed by a brief decrease and a final time-dependent linear increase in cell-associated fluorescence. We interpret these results as representing chelation of outer membrane-bound magnesium by fleroxacin and other quinolones, dissociation of the quinolone-magnesium complex from the outer membrane, and diffusion of the quinolone through both porins and exposed lipid domains on the outer membrane. For a given quinolone, the contribution of the porin and nonporin pathways to total uptake is influenced by the hydrophobicity of the quinolone. PMID:3132091

  5. 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

  6. 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

  7. 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

  8. Antibiotic-loaded, silver core-embedded mesoporous silica nanovehicles as a synergistic antibacterial agent for the treatment of drug-resistant infections.

    PubMed

    Wang, Yao; Ding, Xiali; Chen, Yuan; Guo, Mingquan; Zhang, Yan; Guo, Xiaokui; Gu, Hongchen

    2016-09-01

    Drug-resistant bacterial infections have become one of the most serious risks in public health as they make the conventional antibiotics less efficient. There is an urgent need for developing new generations of antibacterial agents in this field. In this work, a nanoplatform of LEVO-loaded and silver core-embedded mesoporous silica nanovehicles (Ag@MSNs@LEVO) is demonstrated as a synergistic antibacterial agent for the treatment of drug-resistant infections both in vitro and in vivo. The combination of the inner Ag core and the loaded antibiotic drug in mesopores endows the single-particle nanoplatform with a synergistic effect on killing the drug-resistant bacteria. The nanoplatform of Ag@MSNs@LEVO exhibits superior antibacterial activity to LEVO-loaded MSNs (MSNs@LEVO) and silver core-embedded MSNs (Ag@MSNs) in vitro. In the in vivo acute peritonitis model, the infected drug-resistant Escherichia coli GN102 in peritoneal cavity of the mice is reduced by nearly three orders of magnitude and the aberrant pathological feature of spleen and peritoneum disappears after treatment with Ag@MSNs@LEVO. Importantly, this nanopaltform renders no obvious toxic side effect to the mice during the tested time. There is no doubt that this study strongly indicates a promising potential of Ag@MSNs@LEVO as a synergistic and safety therapy tool for the clinical drug-resistant infections. PMID:27294538

  9. 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

  10. Determination of quinolones and fluoroquinolones, tetracyclines and sulfonamides in bovine, swine and poultry liver using LC-MS/MS.

    PubMed

    Martins, Magda Targa; Barreto, Fabiano; Hoff, Rodrigo Barcelos; Jank, Louise; Arsand, Juliana Bazzan; Feijó, Tiago Correa; Schapoval, Elfrides Eva Scherman

    2015-01-01

    Antibacterials are widely used in veterinary medicine. Residues of these drugs can remain in food of animal origin, including bovine liver. This paper describes a fast and simple analytical method for the determination of quinolones and fluoroquinolones, tetracyclines and sulfonamides in bovine liver samples. Deuterated enrofloxacin, sulfapyridine and demeclocycline were used as internal standards. The homogenised liver samples were extracted with acidified acetonitrile. Steps of non-solid-phase extraction (SPE) clean-up and concentration were used in the presented method. The final extracts were analysed by sensitive and selective detection of all components in a single run using LC-MS/MS. Acceptable recoveries between 66% and 110% were obtained. Good linearity (r(2)) above 0.96, considering three different days, for all drugs was achieved in concentrations ranging from 0.0 to 2.0 × the maximum residue limit (MRL). Intraday precision with coefficient of variation (CV%) (n = 6) lower than 14.7% and inter-day precision lower than 18.8% in agreement with European Commission Decision 2002/657/EC were obtained in concentrations ranging from 0.5 to 1.5 MRL. Accuracy was between 86% and 110%. Limits of detection and quantitation, as well as decision limit (CCα) and detection capability (CCβ), were also evaluated. PMID:25686359

  11. White Paper: Recommendations on the Conduct of Superiority and Organism-Specific Clinical Trials of Antibacterial Agents for the Treatment of Infections Caused by Drug-Resistant Bacterial Pathogens

    PubMed Central

    2012-01-01

    There is a critical need for new pathways to develop antibacterial agents to treat life-threatening infections caused by highly resistant bacteria. Traditionally, antibacterial agents have been studied in noninferiority clinical trials that focus on one site of infection (eg, pneumonia, intra-abdominal infection). Conduct of superiority trials for infections caused by highly antibiotic-resistant bacteria represents a new, and as yet, untested paradigm for antibacterial drug development. We sought to define feasible trial designs of antibacterial agents that could enable conduct of superiority and organism-specific clinical trials. These recommendations are the results of several years of active dialogue among the white paper's drafters as well as external collaborators and regulatory officials. Our goal is to facilitate conduct of new types of antibacterial clinical trials to enable development and ultimately approval of critically needed new antibacterial agents. PMID:22891041

  12. 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

  13. 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

  14. Investigation of β-lactam antibacterial drugs, β-lactamases, and penicillin-binding proteins with fluorescence polarization and anisotropy: a review

    NASA Astrophysics Data System (ADS)

    Shapiro, Adam B.

    2016-06-01

    This review covers the uses of fluorescence polarization and anisotropy for the investigation of bacterial penicillin binding proteins (PBPs), which are the targets of β-lactam antibacterial drugs (penicillins, cephalosporins, carbapenems, and monobactams), and of the β-lactamase enzymes that destroy these drugs and help to render bacterial pathogens resistant to them. Fluorescence polarization and anisotropy-based methods for quantitation of β-lactam drugs are also reviewed. A particular emphasis is on methods for quantitative measurement of the interactions of β-lactams and other inhibitors with PBPs and β-lactamases.

  15. 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

  16. Influence of First-Line Antibiotics on the Antibacterial Activities of Acetone Stem Bark Extract of Acacia mearnsii De Wild. against Drug-Resistant Bacterial Isolates

    PubMed Central

    Olajuyigbe, Olufunmiso O.; Coopoosamy, Roger M.

    2014-01-01

    Background. This study was aimed at evaluating the antibacterial activity of the acetone extract of A. mearnsii and its interactions with antibiotics against some resistant bacterial strains. Methods. The antibacterial susceptibility testing was determined by agar diffusion and macrobroth dilution methods while the checkerboard method was used for the determination of synergy between the antibiotics and the extract. Results. The results showed that the susceptibility of the different bacterial isolates was concentration dependent for the extract and the different antibiotics. With the exception of S. marcescens, the inhibition zones of the extract produced by 20 mg/mL ranged between 18 and 32 mm. While metronidazole did not inhibit any of the bacterial isolates, all the antibiotics and their combinations, except for ciprofloxacin and its combination, did not inhibit Enterococcus faecalis. The antibacterial combinations were more of being antagonistic than of being synergistic in the agar diffusion assay. From the macrobroth dilution, the extract and the antibiotics exerted a varied degree of inhibitory effect on the test organisms. The MIC values of the acetone extract which are in mg/mL are lower than those of the different antibiotics which are in μg/mL. From the checkerboard assay, the antibacterial combinations showed varied degrees of interactions including synergism, additive, indifference, and antagonism interactions. While antagonistic and additive interactions were 14.44%, indifference interaction was 22.22% and synergistic interaction was 37.78% of the antibacterial combinations against the test isolates. While the additivity/indifference interactions indicated no interactions, the antagonistic interaction may be considered as a negative interaction that could result in toxicity and suboptimal bioactivity. Conclusion. The synergistic effects of the herbal-drug combinations may be harnessed for the discovery and development of more rational evidence

  17. Detecting metabolic activities of bacteria using a simple carbon nanotube device for high-throughput screening of anti-bacterial drugs.

    PubMed

    Huang, Yinxi; Sudibya, Herry Gunadi; Chen, Peng

    2011-06-15

    In this contribution, we demonstrate a simple carbon nanotube device to electrically detect the presence of bacteria (Escherichai coli) with high sensitivity (<100 cfu/mL) and the glucose triggered metabolic activities of bacteria in real-time. As proof-of-concept demonstration, we also show that this nanoelectronic approach can be employed for high-throughput screening of anti-bacterial drugs. PMID:21570819

  18. Pharmacokinetics: metabolism and renal excretion of quinolones in man.

    PubMed

    Vree, T B; Wijnands, W J; Guelen, P J; Baars, A M; Hekster, Y A

    1986-02-21

    The quinolones are relatively poorly absorbed from the gastrointestinal tract. The elimination proceeds mainly by renal excretion. The half-life of elimination depends on the molecular structure and varies between 2 and 10 h. Impaired kidney function is expected to increase the half-life of elimination, though this effect is not always observed. Since the 4-oxo-metabolites show a higher renal clearance than the parent drug, renal impairment will result in a cumulation of the metabolites in the body. PMID:3960691

  19. The Emergence of Quinolone Resistant Shigella sonnei, Pondicherry, India

    PubMed Central

    2016-01-01

    Ciprofloxacin resistant Shigella sonnei across the globe have been increasing alarmingly. In order to understand the emergence of S.sonnei with respect to ciprofloxacin resistance in our patient population, the following study was carried out. Of the 184 Shigella sp. Isolated from 2012 to 2015, 34 S.sonnei which were confirmed by standard methods and subjected to antimicrobial susceptibility testing were selected. The minimum inhibitory concentrations (MICs) of 16/34 quinolone resistant isolates tested ranged from 4micrograms/ml to 16micrograms/ml for ciprofloxacin, from 16 micrograms/ml to 64 micrograms/ml for ofloxacin and from 16micrograms/ml to 64micrograms/ml for levofloxacin. Sequence determination of the quinolone resistance determining regions of gyrA, gyrB, parC, and parE genes showed mutations in GyrA at Gln69/Trp, Phe71/Ser, Ser72/Pro, Met75/Leu, Ser90/Cys, Met94/Leu, His106/Pro, Asn161/His, Thr163/Ala and in ParC at Ala64/Asp. Among the plasmid-mediated quinolone resistance (PMQRs) targets investigated,qnrB was the most (93.7%) prevalent followed by qnrC (18.7%). None hadqnrA, qnrS and qepA. Two (0.1%) of the isolates harboured theaac(6’)-lb gene. Drug accumulation assay detected the presence of efflux pump activity in 9/15 (60%) among ciprofloxacin resistant isolates. All isolates harboured the ipaH gene followed by ial (17.6%), sen (11.7%), set1A&set1B (5.8%) genes. None had stx1 element. PCR for Enterobacterial repetitive intergenic consensus (ERIC) sequences resulted in 4 unique clusters, of which Type III was the most (44%) dominant but there was no correlation between the ERIC types and the antibiotic resistance pattern or the virulence profile. A documented increase in S.sonnei harbouring the qnrgenes and some unusual genes like set1Aand indicate an ongoing process of horizontal gene transfer. The accumulation of novel mutations in GyrA and ParC in the presence of efflux pump and PMQR genes contributed to the raised MIC to quinolones. These

  20. The Emergence of Quinolone Resistant Shigella sonnei, Pondicherry, India.

    PubMed

    Das, Ankita; Natarajan, Mailan; Mandal, Jharna

    2016-01-01

    Ciprofloxacin resistant Shigella sonnei across the globe have been increasing alarmingly. In order to understand the emergence of S.sonnei with respect to ciprofloxacin resistance in our patient population, the following study was carried out. Of the 184 Shigella sp. Isolated from 2012 to 2015, 34 S.sonnei which were confirmed by standard methods and subjected to antimicrobial susceptibility testing were selected. The minimum inhibitory concentrations (MICs) of 16/34 quinolone resistant isolates tested ranged from 4micrograms/ml to 16micrograms/ml for ciprofloxacin, from 16 micrograms/ml to 64 micrograms/ml for ofloxacin and from 16micrograms/ml to 64micrograms/ml for levofloxacin. Sequence determination of the quinolone resistance determining regions of gyrA, gyrB, parC, and parE genes showed mutations in GyrA at Gln69/Trp, Phe71/Ser, Ser72/Pro, Met75/Leu, Ser90/Cys, Met94/Leu, His106/Pro, Asn161/His, Thr163/Ala and in ParC at Ala64/Asp. Among the plasmid-mediated quinolone resistance (PMQRs) targets investigated,qnrB was the most (93.7%) prevalent followed by qnrC (18.7%). None hadqnrA, qnrS and qepA. Two (0.1%) of the isolates harboured theaac(6')-lb gene. Drug accumulation assay detected the presence of efflux pump activity in 9/15 (60%) among ciprofloxacin resistant isolates. All isolates harboured the ipaH gene followed by ial (17.6%), sen (11.7%), set1A&set1B (5.8%) genes. None had stx1 element. PCR for Enterobacterial repetitive intergenic consensus (ERIC) sequences resulted in 4 unique clusters, of which Type III was the most (44%) dominant but there was no correlation between the ERIC types and the antibiotic resistance pattern or the virulence profile. A documented increase in S.sonnei harbouring the qnrgenes and some unusual genes like set1Aand indicate an ongoing process of horizontal gene transfer. The accumulation of novel mutations in GyrA and ParC in the presence of efflux pump and PMQR genes contributed to the raised MIC to quinolones. These

  1. A New Approach for Early Assessment of the Epileptogenic Potential of Quinolones

    PubMed Central

    Delon, Annie; Pariat, Claudine; Courtois, Philippe; Bouquet, Serge; Couet, William

    1998-01-01

    The epileptogenic potential of pefloxacin and norfloxacin, two quinolone antibiotics, was investigated in vivo in three different animal species by measuring drug concentrations in cerebrospinal fluid (CSF), which is part of the biophase, at the onset of convulsions. Interestingly, the pefloxacin-to-norfloxacin concentration ratios in CSF were virtually constant across the species (7.0, 6.6, and 6.0 in mice, rats, and rabbits, respectively), suggesting that this approach could be used to predict the relative epileptogenic potential of quinolones in humans. PMID:9756792

  2. 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

  3. Gallium(iii) and iron(iii) complexes of quinolone antimicrobials.

    PubMed

    Mjos, Katja Dralle; Cawthray, Jacqueline F; Polishchuk, Elena; Abrams, Michael J; Orvig, Chris

    2016-08-16

    Iron is an essential nutrient for many microbes. According to the "Trojan Horse Hypothesis", biological systems have difficulties distinguishing between Fe(3+) and Ga(3+), which constitutes the antimicrobial efficacy of the gallium(iii) ion. Nine novel tris(quinolono)gallium(iii) complexes and their corresponding iron(iii) analogs have been synthesized and fully characterized. Quinolone antimicrobial agents from three drug generations were used in this study: ciprofloxacin, enoxacin, fleroxacin, levofloxacin, lomefloxacin, nalidixic acid, norfloxacin, oxolinic acid, and pipemidic acid. The antimicrobial efficacy of the tris(quinolono)gallium(iii) complexes was studied against E. faecalis and S. aureus (both Gram-positive), as well as E. coli, K. pneumonia, and P. aeruginosa (all Gram-negative) in direct comparison to the tris(quinolono)iron(iii) complexes and the corresponding free quinolone ligands at various concentrations. For the tris(quinolono)gallium(iii) complexes, no combinational antimicrobial effects between Ga(3+) and the quinolone antimicrobial agents were observed. PMID:27315225

  4. 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

  5. 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

  6. Activation of Macrophages: Establishing a Role for Polysaccharides in Drug Delivery Strategies Envisaging Antibacterial Therapy.

    PubMed

    Rodrigues, Susana; Grenha, Ana

    2015-01-01

    Infectious diseases are an important health concern, as several pathogens have developed the ability to survive inside phagocytic cells (mostly macrophages), encountered at early infection stages, using these cells as trojan horses. In fact, in several cases macrophages have become a nutrient reservoir that helps pathogens to grow in number and spread. It is frequent that conventional therapeutic schedules include long periods of drug intake, at high doses, in some cases leading to severe side effects and clinical relapses due to prolonged intake, along with an increased risk for the development of antibiotic resistances. Therefore, there is a compelling need to develop new therapeutic strategies providing a targeted drug delivery to macrophages. These cells have unique surface receptors that might recognise preferentially several polysaccharide moieties present on the surface of infecting organisms, including in the bacterial cell wall. Benefiting from a similar composition regarding the referred moieties, polysaccharides might be good candidates to compose the matrix of drug carriers aimed at macrophage targeting, as they can use the same recognition pathways of the infecting organisms. This review describes the features and the role of macrophages in infectious conditions, while addressing their potential as therapeutic targets and unravelling the prominent role of polysaccharides as matrix materials of drug delivery systems developed for the therapy of infectious diseases. PMID:26290207

  7. 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

  8. 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

  9. Complestatin exerts antibacterial activity by the inhibition of fatty acid synthesis.

    PubMed

    Kwon, Yun-Ju; Kim, Hyun-Ju; Kim, Won-Gon

    2015-01-01

    Bacterial enoyl-acyl carrier protein (ACP) reductase has been confirmed as a novel target for antibacterial drug development. In the screening of inhibitors of Staphylococcus aureus enoyl-ACP reductase (FabI), complestatin was isolated as a potent inhibitor of S. aureus FabI together with neuroprotectin A and chloropeptin I from Streptomyces chartreusis AN1542. Complestatin and related compounds inhibited S. aureus FabI with IC₅₀ of 0.3-0.6 µM. They also prevented the growth of S. aureus as well as methicillin-resistance S. aureus (MRSA) and quinolone-resistant S. aureus (QRSA), with minimum inhibitory concentrations (MICs) of 2-4 µg/mL. Consistent with its FabI-inhibition, complestatin selectively inhibited the intracellular fatty acid synthesis in S. aureus, whereas it did not affect the macromolecular biosynthesis of other cellular components, such as DNA, RNA, proteins, and the cell wall. Additionally, supplementation with exogenous fatty acids reversed the antibacterial effect of complestatin, demonstrating that it targets fatty acid synthesis. In this study, we reported that complestatin and related compounds showed potent antibacterial activity via inhibiting fatty acid synthesis. PMID:25947917

  10. Antibacterial Drug Discovery Targeting the Lipopolysaccharide Biosynthetic Enzyme LpxC.

    PubMed

    Erwin, Alice L

    2016-01-01

    The enzyme LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase) is broadly conserved across Gram-negative bacteria and is essential for synthesis of lipid A, the membrane anchor of the lipopolysaccharides (LPSs), which are a major component of the outer membrane in nearly all Gram-negative bacteria. LpxC has been the focus of target-directed antibiotic discovery projects in numerous pharmaceutical and academic groups for more than 20 years. Despite intense effort, no LpxC inhibitor has been approved for therapeutic use, and only one has yet reached human studies. This article will summarize the history of LpxC as a drug target and the parallel history of research on LpxC biology. Both academic and industrial researchers have used LpxC inhibitors as tool compounds, leading to increased understanding of the differing mechanisms for regulation of LPS synthesis in Escherichia coli and Pseudomonas aeruginosa. PMID:27235477

  11. 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.

  12. A novel cotton fabric with anti-bacterial and drug delivery properties using SBA-15-NH2/polysiloxane hybrid containing tetracycline.

    PubMed

    Hashemikia, Samaneh; Hemmatinejad, Nahid; Ahmadi, Ebrahim; Montazer, Majid

    2016-02-01

    Here, mesoporous silica particles containing tetracycline were loaded on cotton fabric for possible application on the infected human skin. Amino functionalized mesoporous silica, SBA-15-NH2, was chosen as a safe drug carrier loaded with tetracycline via post impregnation method. Diverse content of the drug loaded silica particles were then attached on the cotton fabric surface using polysiloxane reactive softener as a soft and safe fixing agent. UV-Vis spectroscopy was used to study the drug delivery properties of the mesoporous silica on the treated cotton fabrics. The treated fabric with long drug release properties was selected as the optimized sample. Further analysis was carried out on this sample including anti-bacterial, water contact angle, bending length, mineral content and washing durability. Also, SEM images, EDX patterns, X-Ray spectra and thermal behavior of the optimum sample were studied. The optimized treated sample indicated the gradual release profile of tetracycline in PBS buffer media within 48h along with excellent anti-bacterial efficiency as a good feature for biological application. PMID:26652393

  13. 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

  14. 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

  15. Reduced susceptibility to quinolones among Salmonella serotypes isolated from poultry at slaughter in Venezuela.

    PubMed

    Boscán-Duque, Leonardo A; Arzálluz-Fisher, Ana M; Ugarte, Carmen; Sánchez, Damarys; Wittum, Thomas E; Hoet, Armando E

    2007-09-01

    Today there are recognized global "hot spots" that are areas in which nontyphoid Salmonella serotypes have been reported to have a high prevalence of quinolone resistance. There is concern that resistant strains can be disseminated from these localized geographical areas by travelers or via commercial food products. The objective of this article is to report a high frequency of reduced susceptibility to first- and second-generation quinolones among nontyphoid Salmonella isolates from poultry at slaughter in two processing plants belonging to the largest poultry integration companies in Zulia State, Venezuela. Nearly all (74 of 77; 96.1%) of the isolated strains were resistant to nalidixic acid, and 3.7% were resistant to ciprofloxacin; most (45 of 77; 58%) exhibited reduced susceptibility to ciprofloxacin and norfloxacin (15 of 77; 19.5%). In contrast, all of the isolates were susceptible to beta-lactamic antimicrobial drugs. Ninety-three percent (72 of 77) of the isolates were either Salmonella Parathyphi B or Salmonella Heidelberg, which have been reported as invasive Salmonella. The predominant serotypes in each slaughter plant showed different antimicrobial susceptibilities, only having in common their high resistance to nalidixic acid, suggesting that different clones disseminated in each commercial integration. The detection of high frequency of reduced susceptibility to first- and second-generation quinolones among nontyphoid Salmonella isolates from fresh poultry during processing is noteworthy. Resistance to quinolone drugs will not only make antimicrobial therapy more complicated if foodborne disease results, but also these quinolone-resistant strains can disseminate from this local hot spot to other geographical areas, spreading the resistance against this important antimicrobial drug. PMID:17900079

  16. Characteristics of antibiotic resistance and sequence type of Acinetobacter baumannii clinical isolates in Japan and the antibacterial activity of DS-8587.

    PubMed

    Higuchi, Saito; Shikata, Mototsugu; Chiba, Megumi; Hoshino, Kazuki; Gotoh, Naomasa

    2014-04-01

    DS-8587 is a novel broad-spectrum fluoroquinolone with extended antimicrobial activity against both Gram-positive and Gram-negative pathogens. In this study, we evaluated the antibacterial activity and mechanism of DS-8587 in 31 quinolone-resistant Acinetobacter baumannii clinical isolates. Efflux pump and qnr genes, mutations in quinolone resistance-determining regions of target enzymes, and sequence types determined by multilocus sequence typing were analyzed. Forty-two quinolone-susceptible clinical isolates were analyzed for comparison. For susceptibility testing, DS-8587 exhibited more effective antibacterial activity when compared with ciprofloxacin and levofloxacin. When combined with the efflux pump inhibitor 1-(1-napthylmethyl)-piperazine, the MIC of DS-8587 was less affected when compared with the MIC exhibited by combined ciprofloxacin and 1-(1-napthylmethyl)-piperazine. The efflux pump genes adeA/adeB/adeC and regulatory elements adeR/adeS were detected in 23 of 31 quinolone-resistant isolates. The qnrA/qnrB/qnrS genes were not detected in any A. baumannii isolates analyzed. Mutations in quinolone resistance-determining regions were observed in all 31 quinolone-resistant isolates. Multilocus sequence typing analyses revealed that 22 of 31 quinolone-resistant isolates belonged to ST-2, corresponding to international clonal lineage II. In conclusion, DS-8587 exhibits potent antibacterial activity against quinolone-resistant A. baumannii isolates that harbor mutations in quinolone resistance-determining regions. In the presence of the efflux pump inhibitor 1-(1-napthylmethyl)-piperazine, no significant changes were observed in the MIC for DS-8587. DS-8587 should be considered as a treatment option for A. baumannii including ST-2 strains that are predominant among the quinolone-resistant A. baumannii isolates found in Japan. PMID:24709045

  17. [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

  18. 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

  19. Novel quinolone resistance mutations of the Escherichia coli DNA gyrase A protein: enzymatic analysis of the mutant proteins.

    PubMed Central

    Hallett, P; Maxwell, A

    1991-01-01

    Using the techniques of gap misrepair mutagenesis and site-directed mutagenesis, we have generated two novel quinolone resistance mutations of the Escherichia coli DNA gyrase A protein. DNA sequencing showed these mutations to be Ser-83----Ala and Gln-106----Arg. The mutant proteins were overproduced and purified, and their enzymatic properties were analyzed and compared with those of the wild-type enzyme. With ciprofloxacin and other quinolones, the inhibition of DNA supercoiling, relaxation, and decatenation and the induction of DNA cleavage were investigated for both wild-type and mutant enzymes. In each assay, the mutant enzymes were found to require approximately 10 times more drug to inhibit the reaction or induce cleavage than was the wild-type enzyme. However, the Ca2(+)-directed DNA cleavage reaction was indistinguishable for wild-type and mutant gyrases. We discuss models for the gyrase-mediated bactericidal effects of quinolone drugs. Images PMID:1850970

  20. 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

  1. 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

  2. New developments in antibacterial choice for lower respiratory tract infections in elderly patients.

    PubMed

    Ferrara, Anna Maria; Fietta, Anna Maria

    2004-01-01

    Elderly patients are at increased risk of developing lower respiratory tract infections compared with younger patients. In this population, pneumonia is a serious illness with high rates of hospitalisation and mortality, especially in patients requiring admission to intensive care units (ICUs). A wide range of pathogens may be involved depending on different settings of acquisition and patient's health status. Streptococcus pneumoniae is the most common bacterial isolate in community-acquired pneumonia, followed by Haemophilus influenzae, Moraxella catarrhalis and atypical pathogens such as Chlamydia pneumoniae, Legionella pneumophila and Mycoplasma pneumoniae. However, elderly patients with comorbid illness, who have been recently hospitalised or are residing in a nursing home, may develop severe pneumonia caused by multidrug resistant staphylococci or pneumococci, and enteric Gram-negative bacilli, including Pseudomonas aeruginosa. Moreover, anaerobes may be involved in aspiration pneumonia. Timely and appropriate empiric treatment is required in order to enhance the likelihood of a good clinical outcome, prevent the spread of antibacterial resistance and reduce the economic impact of pneumonia. International guidelines recommend that elderly outpatients and inpatients (not in ICU) should be treated for the most common bacterial pathogens and the possibility of atypical pathogens. The algorithm for therapy is to use either a selected beta-lactam combined with a macrolide (azithromycin or clarithromycin), or to use monotherapy with a new anti-pneumococcal quinolone, such as levofloxacin, gatifloxacin or moxifloxacin. Oral (amoxicillin, amoxicillin/clavulanic acid, cefuroxime axetil) and intravenous (sulbactam/ampicillin, ceftriaxone, cefotaxime) beta-lactams are agents of choice in outpatients and inpatients, respectively. For patients with severe pneumonia or aspiration pneumonia, the specific algorithm is to use either a macrolide or a quinolone in combination

  3. In vitro studies with five quinolones: evidence for changes in relative potency as quinolone resistance rises.

    PubMed Central

    Thomson, K S; Sanders, C C; Hayden, M E

    1991-01-01

    A panel of 203 staphylococci, Enterobacteriaceae, Pseudomonas aeruginosa, and miscellaneous nonfermentative gram-negative bacilli were chosen for their various susceptibilities to ciprofloxacin. On the basis of agar dilution susceptibilities, each of the four taxonomic groups was divided into ciprofloxacin-susceptible, moderately resistant, and highly resistant subgroups, and each subgroup was then further analyzed for its susceptibility to the fluoroquinolones CI-960, CI-990, sparfloxacin, and ofloxacin. Although the MICs of each quinolone increased as ciprofloxacin resistance increased, the potency of CI-960 appeared to increase relative to the potencies of the other quinolones. Similarly, the MICs of sparfloxacin and ofloxacin appeared to be less affected by ciprofloxacin resistance than were the MICs of ciprofloxacin or CI-990. Single-step mutants of representative clinical isolates with different levels of ciprofloxacin resistance were selected to determine whether the study quinolones differed in their propensity to select resistant mutants and whether the presence of preexisting ciprofloxacin resistance influenced the subsequent development of resistance. Each of the five fluoroquinolones and nalidixic acid selected mutants that exhibited generally modest decreases in quinolone susceptibility (4- to 16-fold). However, CI-960 inhibited significantly more mutants (80%) than did the other quinolones (39 to 59%) at a concentration of 1 microgram/ml. The presence of preexisting ciprofloxacin resistance appeared to be associated with higher mutational frequencies in coagulase-negative staphylococci exposed to each of the fluoroquinolones and in Serratia marcescens exposed to nalidixic acid. Preexisting ciprofloxacin resistance did not influence the development of resistance in the strains of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, or Pseudomonas aeruginosa that were studied. The results of this study suggest that quinolones are not affected

  4. 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

  5. Cytotoxic, antibacterial, DNA interaction and superoxide dismutase like activities of sparfloxacin drug based copper(II) complexes with nitrogen donor ligands.

    PubMed

    Patel, Mohan N; Joshi, Hardik N; Patel, Chintan R

    2013-03-01

    The novel neutral mononuclear copper(II) complexes with fluoroquinolone antibacterial drug, sparfloxacin and nitrogen donor heterocyclic ligand have been synthesized and characterized. An antimicrobial efficiency of the complexes has been tested against five different microorganisms and showed diverse biological activity. The interaction of complex with Herring sperm (HS) DNA was investigated using viscosity titration and absorption titration techniques. The results indicate that the complexes bind to DNA by intercalative mode and have rather high DNA-binding constants. DNA cleavage study showed better cleaving ability of the complexes compare to metal salt and standard drug. All the complexes showed good cytotoxic activity with LC(50) values ranging from 4.89 to 11.94 μg mL(-1). Complexes also exhibit SOD-like activity with their IC(50) values ranging from 0.717 to 1.848 μM. PMID:23266675

  6. Cytotoxic, antibacterial, DNA interaction and superoxide dismutase like activities of sparfloxacin drug based copper(II) complexes with nitrogen donor ligands

    NASA Astrophysics Data System (ADS)

    Patel, Mohan N.; Joshi, Hardik N.; Patel, Chintan R.

    2013-03-01

    The novel neutral mononuclear copper(II) complexes with fluoroquinolone antibacterial drug, sparfloxacin and nitrogen donor heterocyclic ligand have been synthesized and characterized. An antimicrobial efficiency of the complexes has been tested against five different microorganisms and showed diverse biological activity. The interaction of complex with Herring sperm (HS) DNA was investigated using viscosity titration and absorption titration techniques. The results indicate that the complexes bind to DNA by intercalative mode and have rather high DNA-binding constants. DNA cleavage study showed better cleaving ability of the complexes compare to metal salt and standard drug. All the complexes showed good cytotoxic activity with LC50 values ranging from 4.89 to 11.94 μg mL-1. Complexes also exhibit SOD-like activity with their IC50 values ranging from 0.717 to 1.848 μM.

  7. Physicochemical properties of quinolone antibiotics in various environments.

    PubMed

    Park, Hyoung-Ryun; Kim, Tae Heung; Bark, Ki-Min

    2002-06-01

    The progress and photosensitivity of quinolone antibiotics are briefly described. By the photolysis of nalidixic acid, the loss of -COOH group is observed. The photoreaction of fluoroquinolones involves heterolytic C-F bond fragmentation. The protonation and divalent cation complexation equilibria are also examined. The spectroscopic properties of these drugs are intensively investigated in biological mimetic systems such as AOT reverse micelle, and H(2)O-CH(3)OH and H(2)O-CH(3)CN mixed solvents. For ofloxacin and norfloxacin, the excited-state intramolecular charge transfer (ICT) is observed. So, fluorescence spectra exhibit reverse solvatochromism in mixed solvents. The change of radiative and non-radiative rate constant can also be explained using this ICT. The influence of dielectric effects of solvent is more significant compared with the specific hydrogen bonding interaction. Theoretical treatments support all of these results. PMID:12204471

  8. Quinolone and macrolide resistance in Campylobacter jejuni and C. coli: resistance mechanisms and trends in human isolates.

    PubMed Central

    Engberg, J.; Aarestrup, F. M.; Taylor, D. E.; Gerner-Smidt, P.; Nachamkin, I.

    2001-01-01

    The incidence of human Campylobacter jejuni and C. coli infections has increased markedly in many parts of the world in the last decade as has the number of quinolone-resistant and, to a lesser extent, macrolide-resistant Campylobacter strains causing infections. We review macrolide and quinolone resistance in Campylobacter and track resistance trends in human clinical isolates in relation to use of these agents in food animals. Susceptibility data suggest that erythromycin and other macrolides should remain the drugs of choice in most regions, with systematic surveillance and control measures maintained, but fluoroquinolones may now be of limited use in the empiric treatment of Campylobacter infections in many regions. PMID:11266291

  9. 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

  10. 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 µg/mL, respectively. Further citrinin (1) displayed significant activity against the pathogenic yeast Cryptococcus neoformans (MIC 3.90 µg/mL), and exhibited cytotoxicity against brine shrimp larvae LD50 of 96 µg/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

  11. 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

  12. ANTIBACTERIAL PROPERTIES OF THE CFTR POTENTIATOR IVACAFTOR

    PubMed Central

    Reznikov, Leah R.; Abou Alaiwa, Mahmoud H.; Dohrn, Cassie L.; Gansemer, Nick D.; Diekema, Daniel J.; Stoltz, David A.; Welsh, Michael J.

    2016-01-01

    Background Ivacaftor increases CFTR channel activity and improves pulmonary function for individuals bearing a G551D mutation. Because ivacaftor structurally resembles quinolone antibiotics, we tested the hypothesis that ivacaftor possesses antibacterial properties. Methods Bioluminescence, colony forming unit, and minimal inhibitory concentration assays were used to assess viability of Staphylococcus aureus, Pseudomonas aeruginosa and multiple clinical microbial isolates. Results Ivacaftor induced a dose-dependent reduction in bioluminescence of S. aureus and decreased the number of colony forming units. We observed a similar but less robust effect in P. aeruginosa following outer membrane permeabilization. Ivacaftor inhibited the growth of respiratory isolates of S. aureus and Streptococcus pneumoniae and exhibited positive interactions with antibiotics against lab and respiratory strains of S. aureus and S. pneumoniae. Conclusion These data indicate that ivacaftor exhibits antibacterial properties and raise the intriguing possibility that ivacaftor might have an antibiotic effect in people with CF. PMID:24618508

  13. Activity of quinolones against gram-positive cocci: clinical features.

    PubMed

    Giamarellou, H

    1995-01-01

    The potential role of the commercially available fluoroquinolones in the treatment of Gram-positive infections is discussed on the basis of data obtained from animal experiments and clinical trials. In respiratory tract infections, and particularly in community-acquired pneumonia, it is evident that the presently available quinolones cannot be prescribed empirically as first-line therapy because of their borderline activity against Streptococcus pneumoniae and anaerobes. Reports of pneumococcal seeding in other tissues during quinolone therapy render their administration a debatable issue. Experience in endocarditis is limited to the use of ciprofloxacin plus rifampicin in intravenous drug users with right-sided Staphylococcus aureus endocarditis. Patients with staphylococcal osteomyelitis are included among cases of other bone infections. In noncontrolled studies ciprofloxacin, ofloxacin and pefloxacin attained a staphylococcal eradication rate ranging from 70 to 100%, while the addition of rifampicin has been proven to reduce the emergence of resistant mutants during therapy. In soft tissue and skin structure infections that also involve Gram-negative bacteria, ciprofloxacin and ofloxacin eradicated 72.6 and 89% of staphylococci, respectively; however, the presence of diabetes or vascular disease compromised the success of treatment. In staphylococcal peritonitis complicating continuous ambulatory peritoneal dialysis, results with ciprofloxacin given intravenously or intraperitoneally were promising. In infections in neutropenic hosts, success of prophylaxis or therapy is still not clear, since colonisation and breakthrough bacteraemias with viridans streptococci and staphylococci have been reported. Furthermore, therapeutic results are compromised by the low response rate in Gram-positive infections. Despite the reported clinical efficacy of the newer fluoroquinolones, physicians should be alerted to the emergence of staphylococci resistant to fluoroquinolones

  14. 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

  15. Isoprenoid biosynthesis as a target for antibacterial and antiparasitic drugs: phosphonohydroxamic acids as inhibitors of deoxyxylulose phosphate reducto-isomerase

    PubMed Central

    2004-01-01

    Isoprenoid biosynthesis via the methylerythritol phosphate pathway is a target against pathogenic bacteria and the malaria parasite Plasmodium falciparum. 4-(Hydroxyamino)-4-oxobutylphosphonic acid and 4-[hydroxy(methyl)amino]-4-oxobutyl phosphonic acid, two novel inhibitors of DXR (1-deoxy-D-xylulose 5-phosphate reducto-isomerase), the second enzyme of the pathway, have been synthesized and compared with fosmidomycin, the best known inhibitor of this enzyme. The latter phosphonohydroxamic acid showed a high inhibitory activity towards DXR, much like fosmidomycin, as well as significant antibacterial activity against Escherichia coli in tests on Petri dishes. PMID:15473867

  16. Metal complexes of quinolone antibiotics and their applications: an update.

    PubMed

    Uivarosi, Valentina

    2013-01-01

    Quinolones are synthetic broad-spectrum antibiotics with good oral absorption and excellent bioavailability. Due to the chemical functions found on their nucleus (a carboxylic acid function at the 3-position, and in most cases a basic piperazinyl ring (or another N-heterocycle) at the 7-position, and a carbonyl oxygen atom at the 4-position) quinolones bind metal ions forming complexes in which they can act as bidentate, as unidentate and as bridging ligand, respectively. In the polymeric complexes in solid state, multiple modes of coordination are simultaneously possible. In strongly acidic conditions, quinolone molecules possessing a basic side nucleus are protonated and appear as cations in the ionic complexes. Interaction with metal ions has some important consequences for the solubility, pharmacokinetics and bioavailability of quinolones, and is also involved in the mechanism of action of these bactericidal agents. Many metal complexes with equal or enhanced antimicrobial activity compared to the parent quinolones were obtained. New strategies in the design of metal complexes of quinolones have led to compounds with anticancer activity. Analytical applications of complexation with metal ions were oriented toward two main directions: determination of quinolones based on complexation with metal ions or, reversely, determination of metal ions based on complexation with quinolones. PMID:24029748

  17. 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

  18. Fluorimetric study of the interaction between human serum albumin and quinolones-terbium complex and its application

    NASA Astrophysics Data System (ADS)

    Wang, Yusheng; Feng, Lin; Jiang, Chongqiu

    2005-10-01

    A highly sensitive spectrofluorimetric method is proposed for determination of human serum albumin (HSA) and some quinolone drugs. Using quinolones-terbium (Tb 3+) complex as a fluorescent probe, in the buffer solution of pH 7.8, HSA can remarkably enhance the fluorescence intensity of the quinolones-Tb 3+ complex at 545 nm and the enhanced fluorescence intensity of Tb 3+ ion is in proportion to the concentration of HSA and quinolone drugs. Optimum conditions for the determination of HSA were also investigated. The linear ranges and limits of detection are 8.0 × 10 -9 to 8.0 × 10 -8 mol L -1, 4.20 × 10 -9 mol L -1 (for HSA); 1.0 × 10 -6 to 4.0 × 10 -6 mol L -1, 1.87 × 10 -8 mol L -1 (for norfloxacin) and 1.0 × 10 -7 to 1.0 × 10 -6 mol L -1, 4.82 × 10 -8 mol L -1 (for enoxacine), respectively. This method is simple, practical and relatively free interference from coexisting substances, as well as much more sensitive than most of the existing assays.

  19. 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

  20. Apigenin as an anti-quinolone-resistance antibiotic.

    PubMed

    Morimoto, Yuh; Baba, Tadashi; Sasaki, Takashi; Hiramatsu, Keiichi

    2015-12-01

    We previously reported the first 'reverse antibiotic' (RA), nybomycin (NYB), which showed a unique antimicrobial activity against Staphylococcus aureus strains. NYB specifically suppressed the growth of quinolone-resistant S. aureus strains but was not effective against quinolone-susceptible strains. Although NYB was first reported in 1955, little was known about its unique antimicrobial activity because it was before the synthesis of the first quinolone ('old quinolone'), nalidixic acid, in 1962. Following our re-discovery of NYB, we looked for other RAs among natural substances that act on quinolone-resistant bacteria. Commercially available flavones were screened against S. aureus, including quinolone-resistant strains, and their minimum inhibitory concentrations (MICs) were compared using the microbroth dilution method. Some of the flavones screened showed stronger antimicrobial activity against quinolone-resistant strains than against quinolone-susceptible ones. Amongst them, apigenin (API) was the most potent in its RA activity. DNA cleavage assay showed that API inhibited DNA gyrase harbouring the quinolone resistance mutation gyrA(Ser84Leu) but did not inhibit 'wild-type' DNA gyrase that is sensitive to levofloxacin. An API-susceptible S. aureus strain Mu50 was also selected using agar plates containing 20mg/L API. Whole-genome sequencing of selected mutant strains was performed and frequent back-mutations (reverse mutations) were found among API-resistant strains derived from the API-susceptible S. aureus strains. Here we report that API represents another molecular class of natural antibiotic having RA activity against quinolone-resistant bacteria. PMID:26526895

  1. [Simultaneous determination of quinolones in foods by LC/MS/MS].

    PubMed

    Hatano, Kazuhiro

    2004-10-01

    A simple method was developed for the simultaneous determination of seven quinolones (enoxacin, ofloxacin, ciprofloxacin, danofloxacin, lomefloxacin, enrofloxacin and sarafloxacin) in foods using liquid chromatography coupled with electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). The seven quinolones were extracted with acetonitrile containing 0.2% formic acid, and the extracted solution was cleaned up on a C18 cartridge. The extract was diluted with 5 mmol/L IPCC-MS3 for injection into the LC-ESI-MS/MS. The LC separation was carried out on an ODS column with gradient elution of 5 mmol/L IPCC-MS3-acetonitrile as the mobile phase. Mass spectral acquisition was done in the positive ion mode by applying selected reaction monitoring (SRM). The recoveries of the seven quinolones were mostly greater than 60% from foods fortified at 10 ng/g. The detection limits in foods were 2 ng/g for enoxacin and ciprofloxacin, and 1 ng/g for the other drugs. Twenty cattle muscle, 7 swine muscle, 9 chicken muscle, 16 milk, 19 prawn and 20 broiled eel samples from retail markets were analyzed by this method. Enrofloxacin and its metabolite ciprofloxacin were detected in 9 broiled eel at the level of trace (tr)-34 ng/g and tr-10 ng/g, respectively. PMID:15678937

  2. Should antibacterials be deregulated?

    PubMed

    Rovira, J; Figueras, M; Segú, J L

    1998-05-01

    Deregulation of antibacterials is a recurrent topic in the debate on pharmaceutical policy. This article focuses on one aspect of pharmaceutical regulation, namely the requirement of a medical prescription for purchasing antibacterials. However, a strategy of deregulation should not only concern the switch from prescription-only status to nonprescription status for a given drug, but should consider some complementary measures to minimise potentially harmful effects on health and costs. Risk-benefit and economic evaluations, which are possible approaches to assess the convenience of antibacterial deregulation, force the empirical evidence, the assumptions, as well as the value judgements on which the options are evaluated, to be made explicit. We outline the basic traits of an economic-evaluation approach to assess the issues related to the public interest and the feasibility of a deregulation policy. However, the answer cannot be a generic one, but should address the question for each particular country, and for each antibacterial and indication. Given the limitations of existing evidence on that issue, a tentative research agenda is also proposed. PMID:10180749

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. Non-competitive inhibition of GABAA responses by a new class of quinolones and non-steroidal anti-inflammatories in dissociated frog sensory neurones.

    PubMed Central

    Yakushiji, T.; Shirasaki, T.; Akaike, N.

    1992-01-01

    1. The interaction of a new class of quinolone antimicrobials (new quinolones) and non-steroidal anti-inflammatory agents (NSAIDs) with the GABAA receptor-Cl- channel complex was investigated in frog sensory neurones by use of the internal perfusion and 'concentration clamp' techniques. 2. The new quinolones and the NSAIDs (both 10(-6)-10(-5) M) had little effect on the GABA-induced chloride current (ICI) when applied separately. At a concentration of 10(-4) M the new quinolones, and to a lesser degree the NSAIDs, produced some suppression of the GABA response. 3. The co-administration of new quinolones and some NSAIDs (10(-6)-10(-14) M) resulted in a marked suppression of the GABA response. The size of this inhibition was dependent on the concentration of either the new quinolone or the NSAID tested. The inhibitory potency of new quinolones in combination with 4-biphenylacetic acid (BPAA) was in rank order norfloxacin (NFLX) much greater than enoxacin (ENX) greater than ciprofloxancin (CPFX) much greater than ofloxacin (OFLX), and that of NSAIDs in combination with ENX was BPAA much greater than indomethacin = ketoprofen greater than naproxen greater than ibuprofen greater than pranoprofen. Diclofenac, piroxicam and acetaminophen did not affect GABA responses in the presence of ENX. 4. In the presence of ENX or BPAA, there was a small shift to the right of the concentration-response curve for GABA without any effect on the maximum response. However, the co-administration of these drugs suppressed the maximum of the GABA concentration-response curve, indicating a non-competitive inhibition, for which no voltage-dependency was observed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1317734

  9. 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

  10. The novel antibacterial drug XF-70 is a potent inhibitor of Staphylococcus aureus infection of the burn wound.

    PubMed

    Hurtuk, Michael G; He, L-K; Szilagyi, Andrea; Gamelli, Richard L; Hecht, David W; Kennedy, Richard H; Rhys-Williams, William; Love, William G; Shankar, Ravi

    2010-01-01

    The authors report the findings of in vivo studies of XF-70 (a novel, dicationic porphyrin) against Staphylococcus aureus in a murine model of a burn wound infection. Mice received a 15% total body scald burn wound, which were inoculated with S. aureus (1.8 x 10 CFU). After 24 hours, escharectomies were performed and groups (n = 8) received single or two doses (6 hours apart) of XF-70* (100 microg/wound) or silver sulfadiazine, Acticoat, or saline applied topically. Viable bacteria were quantified from homogenized burn tissue biopsies and the spleen by plating dilutions onto agar plates and CFU determination. A single dose of XF-70 reduced bacterial burden by 98.77% (untreated: 2.78 +/- 2.96 x 10 CFU/g vs XF-70 treated: 3.4 +/- 0.19 x 10 CFU/g, P < .01). Two XF-70 doses reduced the growth of S. aureus by 99.96% (1.2 +/- 0.6 x 10 CFU/g, P < .01). These results were similar to the results obtained from commonly used topical antibacterials silver sulfadiazine and Acticoat. The spleens of mice treated with saline had a robust growth of S. aureus (7.0 +/- 1.97 x 10 CFU/g) whereas those treated with one or two XF-70 doses grew only 3.5 +/- 0.002 x 10 CFU/g and 5.7 +/- 0.002 x 10 CFU/g, respectively, a significant (P < .001) reduction in S. aureus dissemination. Single and multiple doses of XF-70 were effective in controlling S. aureus growth in burn wounds and inhibited systemic dissemination of S. aureus. Early treatment of burn wounds with XF-70 may be effective in slowing bacterial dissemination to other tissues. PMID:20453736

  11. 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

  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. Antibacterial Applications of Nanodiamonds.

    PubMed

    Szunerits, Sabine; Barras, Alexandre; Boukherroub, Rabah

    2016-04-01

    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

  14. 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

    ... of care and unmet need; clinical trial endpoints, including exacerbation and patient-reported outcomes; and clinical trial design elements, including duration of treatment and patient followup. FDA... HUMAN SERVICES Food and Drug Administration Issues in the Design of Clinical Trials of...

  15. [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

  16. Electrochemical screening of the indole/quinolone derivatives as potential protein kinase CK2 inhibitors.

    PubMed

    Martić, Sanela; Tackenburg, Stefanie; Bilokin, Yaroslav; Golub, Andriy; Bdzhola, Volodymyr; Yarmoluk, Sergiy; Kraatz, Heinz-Bernhard

    2012-02-15

    An electrochemical method based on the bioorganometallic Fc-ATP cosubstrate for kinase-catalyzed phosphorylation reactions was used for monitoring casein kinase 2 (CK2) phosphorylations in the absence and presence of five indole/quinolone-based potential inhibitors. Fc-phosphorylation of immobilized peptide RRRDDDSDDD on Au surfaces resulted in a current density at approximately 460 ± 10 mV. An electrochemical redox signal was significantly decreased in the presence of inhibitors. In addition, the electrochemical signal was concentration dependent with respect to the potential inhibitors 1 to 5, which proved to be viable CK2 drug targets with estimated IC₅₀ values in the nanomolar range. PMID:22178909

  17. Antibacterial activity of novel cationic peptides against clinical isolates of multi-drug resistant Staphylococcus pseudintermedius from infected dogs.

    PubMed

    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 (α-helical peptide consisting exclusively of arginine and tryptophan) with minimum inhibitory concentration50 (MIC50) of 1 µM and MIC90 of 2 µM. RR (short anti-inflammatory peptide) and IK8 "D isoform" demonstrated good antimicrobial activity with MIC50 of 4 µM and MIC90 of 8 µM. Penetratin and (KFF)3K (two cell penetrating peptides) were the least effective with MIC50 of 8 µM and MIC90 of 16 µM. 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

  18. 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 (α-helical peptide consisting exclusively of arginine and tryptophan) with minimum inhibitory concentration50 (MIC50) of 1 µM and MIC90 of 2 µM. RR (short anti-inflammatory peptide) and IK8 “D isoform” demonstrated good antimicrobial activity with MIC50 of 4 µM and MIC90 of 8 µM. Penetratin and (KFF)3K (two cell penetrating peptides) were the least effective with MIC50 of 8 µM and MIC90 of 16 µM. 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

  19. Confirmatory and quantitative analysis using experimental design for the extraction and liquid chromatography-UV, liquid chromatography-mass spectrometry and liquid chromatography-mass spectrometry/mass spectrometry determination of quinolones in turkey muscle.

    PubMed

    Clemente, M; Hermo, M P; Barrón, D; Barbosa, J

    2006-12-01

    The aim of this work is to established methods for determination of quinolones (ciprofloxacin, danofloxacin, enrofloxacin, difloxacin and flumequine), regulated by European Union, and sarafloxacin in turkey muscle. An experimental design has been applied for the optimization of the factors that influence the extraction of quinolones from turkey muscle in order to determine the experimental conditions for their extraction with high recoveries. Liquid chromatography with ultraviolet detection (LC-UV), liquid chromatography-mass spectrometry (LC-MS) and liquid chromatography tandem mass spectrometry (LC-MS/MS) have been used for the simultaneous quantification of quinolones antibiotics in turkey muscle. The proposed methods have been validated according to the Food Drugs Administration guideline and presents the limit of quantification below the maximum residue limits established by the European Union for quinolones in turkey muscle. The methods developed have been applied to quantification of enrofloxacin and its main metabolite ciprofloxacin in samples of turkey muscle obtained from animals treated with enrofloxacin. PMID:17027811

  20. 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

  1. Association of mutation patterns in GyrA and ParC genes with quinolone resistance levels in lactic acid bacteria.

    PubMed

    Li, Shaoying; Li, Zhen; Wei, Wan; Ma, Chunyan; Song, Xiaomin; Li, Shufen; He, Wenying; Tian, Jianjun; Huo, Xiaoyan

    2015-02-01

    The quinolone resistance of 19 lactic acid bacterial strains belonging to the genera Enterococcus and Lactobacillus isolated from the natural fermented koumiss and yoghurt were investigated. The objective of this study was to determine the quinolone resistance levels and to explore the association of the resistance with the mutation patterns in gyrA and parC genes, as is currently recommended by the Food and Agriculture Organization/World Health Organization Joint Expert Committee in Guidelines for Evaluation of Probiotics in Food for probiotic lactic acid bacteria drug resistance in 2001. The Oxford Cup method and double-tube dilution method were used to determine the quinolone resistance levels of the isolated strains. Generally, all of the 19 strains showed resistance towards norfloxacin and ciprofloxacin when the Oxford cup method was used, whereas the incidence was lower (to norfloxacin 89.5% and to ciprofloxacin 68.4%) when minimum inhibitory concentration breakpoints (CLSI M100-S23) were tested. Furthermore, gene sequencing was conducted on gyrA and parC of topoisomerase II of these isolated strains. The genetic basis for quinolone resistance may be closely related to mutations in gyrA genes as there were 10 mutation sites in amino-acid sequences encoded by gyrA genes in 10 quinolone resistance strains and 14 mutation sites in Enterococcus durans HZ28, whereas no typical mutations were detected in parC genes. PMID:25204345

  2. 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.

  3. Antibacterials in Household Products

    MedlinePlus

    ... products such as soaps, detergents, health and skincare products and household cleaners. How do antibacterials work? ♦ Antibacterials may be ... contain triclosan or other biocide agents? Antibacterials in household products Are there any risks associated with triclosan-containing ...

  4. Repositioning of Endonuclear Receptors Binders as Potential Antibacterial and Antifungal Agents. Eptyloxìm: A Potential and Novel Gyrase B and Cytochrome Cyp51 Inhibitor.

    PubMed

    Carrieri, Antonio; L'Abbate, Maria; Di Chicco, Mariangela; Rosato, Antonio; Carbonara, Giuseppe; Fracchiolla, Giuseppe

    2016-09-01

    A novel class of antibacterial and antifungal agents is here identified by means of dockings and virtual screening techniques. Biological data proved the initial effort, formulated on the structure similarity of nuclear receptors binders with known quinolones or thiazole derivatives, to reposition PPARs agonists as likely bacterial type II topoisomerases inhibitors. PMID:27546036

  5. Non-competitive inhibition of GABAA responses by a new class of quinolones and non-steroidal anti-inflammatories in dissociated frog sensory neurones.

    PubMed

    Yakushiji, T; Shirasaki, T; Akaike, N

    1992-01-01

    1. The interaction of a new class of quinolone antimicrobials (new quinolones) and non-steroidal anti-inflammatory agents (NSAIDs) with the GABAA receptor-Cl- channel complex was investigated in frog sensory neurones by use of the internal perfusion and 'concentration clamp' techniques. 2. The new quinolones and the NSAIDs (both 10(-6)-10(-5) M) had little effect on the GABA-induced chloride current (ICI) when applied separately. At a concentration of 10(-4) M the new quinolones, and to a lesser degree the NSAIDs, produced some suppression of the GABA response. 3. The co-administration of new quinolones and some NSAIDs (10(-6)-10(-14) M) resulted in a marked suppression of the GABA response. The size of this inhibition was dependent on the concentration of either the new quinolone or the NSAID tested. The inhibitory potency of new quinolones in combination with 4-biphenylacetic acid (BPAA) was in rank order norfloxacin (NFLX) much greater than enoxacin (ENX) greater than ciprofloxancin (CPFX) much greater than ofloxacin (OFLX), and that of NSAIDs in combination with ENX was BPAA much greater than indomethacin = ketoprofen greater than naproxen greater than ibuprofen greater than pranoprofen. Diclofenac, piroxicam and acetaminophen did not affect GABA responses in the presence of ENX. 4. In the presence of ENX or BPAA, there was a small shift to the right of the concentration-response curve for GABA without any effect on the maximum response. However, the co-administration of these drugs suppressed the maximum of the GABA concentration-response curve, indicating a non-competitive inhibition, for which no voltage-dependency was observed.5. Simultaneous administration of ENX and BPAA also suppressed pentobarbitone (PB)-gated Icl. On the other hand, both PB and phenobarbitone reversed the inhibition of GABA-induced Ic, by coadministration of ENX and BPAA.6. The effect on GABAA responses of co-administration of new quinolones and NSAIDs was not via an interaction with

  6. Multiresidue determination of quinolone and fluoroquinolone antibiotics in fish and shrimp by liquid chromatography/tandem mass spectrometry.

    PubMed

    Dufresne, Guy; Fouquet, Andre; Forsyth, Don; Tittlemier, Sheryl A

    2007-01-01

    A multiresidue method was developed to measure low levels of 8 fluoroquinolones (norfloxacin, ofloxacin, danofloxacin, ciprofloxacin, desethylene ciprofloxacin, enrofloxacin, sarafloxacin, and difloxacin) and 4 quinolones (oxolinic acid, flumequine, nalidixic acid, and piromidic acid). Method detection limits range from 0.1 ng/g for quinolones to 0.4 ng/g for fluoroquinolones. Average recoveries range from 57 to 96%, depending on analyte and commodity; relative standard deviations are all less than 18%. The drugs are extracted from tissues using a mixture of ethanol and 1% acetic acid, diluted in aqueous HCI, and defatted by extraction with hexane. The compounds are further isolated using cation-exchange solid-phase extraction and measured using liquid chromatography with electrospray tandem mass spectrometry detection. The method has been evaluated and applied to the analysis of salmon, trout, and shrimp. Detectable residues were observed in 10 out of 73 samples, at concentrations ranging from 0.28 to 16 ng/g. PMID:17474531

  7. 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.

  8. 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

  9. Quinolone-resistant mutants of escherichia coli DNA topoisomerase IV parC gene.

    PubMed Central

    Kumagai, Y; Kato, J I; Hoshino, K; Akasaka, T; Sato, K; Ikeda, H

    1996-01-01

    Escherichia coli quinolone-resistant strains with mutations of the parC gene, which codes for a subunit of topoisomerase IV, were isolated from a quinolone-resistant gyrA mutant of DNA gyrase. Quinolone-resistant parC mutants were also identified among the quinolone-resistant clinical strains. The parC mutants became susceptible to quinolones by introduction of a parC+ plasmid. Introduction of the multicopy plasmids carrying the quinolone-resistant parC mutant gene resulted in an increase in MICs of quinolones for the parC+ and quinolone-resistant gyrA strain. Nucleotide sequences of the quinolone-resistant parC mutant genes were determined, and missense mutations at position Gly-78, Ser-80, or Glu-84, corresponding to those in the quinolone-resistance-determining region of DNA gyrase, were identified. These results indicate that topoisomerase IV is a target of quinolones in E. coli and suggest that the susceptibility of E. coli cells to quinolones is determined by sensitivity of the targets, DNA gyrase and topoisomerase IV. PMID:8851598

  10. The effects of quinolones and NSAIDs upon GABA-evoked currents recorded from rat dorsal root ganglion neurones.

    PubMed

    Halliwell, R F; Davey, P G; Lambert, J J

    1991-02-01

    Recent animal studies have demonstrated a proconvulsant effect of certain quinolone and non-steroidal anti-inflammatory drug combinations. Radioligand binding experiments have indicated that these actions may be mediated by antagonism of the GABAA receptor. The present study has further investigated this hypothesis in a functional assay by examining the effects of the quinolones ciprofloxacin and ofloxacin alone and in combination with either fenbufen or biphenyl acetic acid (BPAA) upon GABA-evoked currents recorded from voltage-clamped rat dorsal root ganglion neurones (DRG) maintained in cell culture. GABA-evoked whole cell currents were weakly but dose-dependently (30 microM-1 mM) reduced in the presence of ciprofloxacin and ofloxacin. The IC50 for ciprofloxacin was 100 microM but greater than 1 mM for ofloxacin. Application of either fenbufen (100 microM) or BPAA (100 microM) alone produced little effect on the GABA-evoked currents. However, the inhibitory action of ciprofloxacin was enhanced in the presence of 100 microM fenbufen by approximately five-fold whereas the antagonism of GABA responses by ofloxacin was unaffected. In contrast, BPAA (100 microM) had a dramatic effect on the inhibitory actions of both antibiotics such that the IC50 for ciprofloxacin and ofloxacin was reduced to 0.03 and 0.3 microM respectively. The present results support earlier binding studies and extend them by demonstrating electrophysiologically a potent quinolone/NSAID drug interaction at the GABAA receptor. The mechanism(s) of this novel interaction remains to be determined. These results are commensurate with clinical observations of an increased risk of fits in patients prescribed certain quinolones together with certain NSAIDs. PMID:1647389

  11. In-vitro activity of newer quinolones against aerobic bacteria.

    PubMed

    Auckenthaler, R; Michéa-Hamzehpour, M; Pechère, J C

    1986-04-01

    Nalidixic and five newer 4-quinolones, ciprofloxacin, enoxacin, norfloxacin, ofloxacin and pefloxacin were tested against 576 recent clinical aerobic bacterial isolates. The 4-quinolones were regularly active (MIC90 less than 4 mg/l) against the following bacteria: Staphylococcus aureus, S. epidermidis, S. saprophyticus, different Enterobacteriaceae, Haemophilus influenzae, Campylobacter jejuni, Pseudomonas aeruginosa, Agrobacter spp., Aeromonas spp., Plesiomonas spp., Neisseria meningitidis. Other bacteria were usually intermediately susceptible or resistant: different streptococci, Listeria monocytogenes, Nocardia asteroides, P. maltophilia, Achromobacter xylosoxydans and Alcaligenes denitrificans. Ciprofloxacin was the most potent compound, followed by ofloxacin and pefloxacin, norfloxacin and enoxacin being less active. All the 4-quinolones were much more active than nalidixic acid. The MBC/MIC ratios of the 4-quinolones were between 1 and 2 with a majority of strains, and between 2 and 3 with Streptococcus agalactiae, Str. faecalis and L. monocytogenes. A two- to eight-fold increase of MIC was observed by increasing the inoculum 10,000-fold with most of the strains tested. Susceptible bacterial population of Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens and P. aeruginosa contained more clones resistant to nalidixic acid (10(4) to 10(8) at four times the MIC) than to 4-quinolones (10(5) to 10(9) at four times the MIC). Supplementing the media with MgSO4 produced smaller inhibition zone diameters with a disc diffusion method than those obtained with non-supplemented agar, with all quinolone or strains. Less regular effect, or no effect was obtained after supplementation with ZnSO4 or Ca(NO3)2. PMID:2940214

  12. Quinolone Resistance Mechanisms Among Salmonella enterica in Malaysia.

    PubMed

    Thong, Kwai Lin; Ngoi, Soo Tein; Chai, Lay Ching; Teh, Cindy Shuan Ju

    2016-06-01

    The prevalence of quinolone-resistant Salmonella enterica is on the rise worldwide. Salmonella enterica is one of the major foodborne pathogens in Malaysia. Therefore, we aim to investigate the occurrence and mechanisms of quinolone resistance among Salmonella strains isolated in Malaysia. A total of 283 Salmonella strains isolated from food, humans, and animals were studied. The disk diffusion method was used to examine the quinolone susceptibility of the strains, and the minimum inhibitory concentration (MIC) values of nalidixic acid and ciprofloxacin were also determined. DNA sequencing of the quinolone resistance-determining regions (QRDRs) of gyrase and topoisomerase IV genes and the plasmid-borne qnr genes was performed. The transfer of the qnr gene was examined through transconjugation experiment. A total of 101 nalidixic acid-resistant Salmonella strains were identified. In general, all strains were highly resistant to nalidixic acid (average MICNAL, 170 μg/ml). Resistance to ciprofloxacin was observed in 30.7% of the strains (1 ≤ MICCIP ≤ 2 μg/ml). Majority of the strains contained missense mutations in the QRDR of gyrA (69.3%). Silent mutations were frequently detected in gyrB (75.2%), parC (27.7%), and parE (51.5%) within and beyond the QRDRs. Novel mutations were detected in parC and parE. The plasmid-borne qnrS1 variant was found in 36.6% of the strains, and two strains were found to be able to transfer the qnrS1 gene. Overall, mutations in gyrA and the presence of qnrS1 genes might have contributed to the high level of quinolone resistance among the strains. Our study provided a better understanding on the status of quinolone resistance among Salmonella strains circulating in Malaysia. PMID:26683630

  13. [Intra-abdominal infection and new quinolones].

    PubMed

    Gnocchi, C A

    1999-01-01

    Intra-abdominal infection is defined as the presence of an infectious process within the peritoneal cavity. It may be local or have a systemic consequence generating multiple organic disfunction. Most of the studies report a mortality of 30% in severe intra-abdominal infection. Secondary peritonitis is caused by the loss of integrity of the gastrointestinal apparatus, which contaminates with pathogens the peritoneal cavity. Invariably they are polymicrobial infections, mostly due to facultative anaerobic and anaerobic Gram negative bacilli. Prognosis of peritonitis depends on the struggle between two forces: local and systemic immunity of the host and the volume, nature and length of the contamination. Microorganisms and their products estimulate cellular defenses in the host and activate numerous inflammatory mediators responsible for sepsis. Antibiotic treatment of secondary peritonitis must act mainly against Escherichia coli and Bacteroides fragilis. The adequate and early empirical administration of antibiotics against these bacteria is well established. It is necessary to consider if the infection is localized or generalized and if it is accompanied or not by organic disfunction. It also has to be taken into account if peritonitis is community or hospital-acquired when choosing the antibiotic scheme. In community-acquired peritonitis with low to moderate infections a combination of metronidazole-ceftriaxone, metronidazole-gentamycin or a monodrug like ampicillin-sulbactam may be used. In severe hospital-acquired peritonitis imipenem or the combination piperacillin-tazobactam are effective. New quinolones such as trovafloxacin or clinafloxacin, with excellent activity against aerobes and anaerobes producing intra-abdominal infections, may be effective. Future clinical trials are needed to determine their utility. Tertiary peritonitis represent a systemic inflammatory response with multiorganic failure due to the uncontrolled activation of the inflammatory

  14. A New-Class Antibacterial-Almost. Lessons in Drug Discovery and Development: A Critical Analysis of More than 50 Years of Effort toward ATPase Inhibitors of DNA Gyrase and Topoisomerase IV.

    PubMed

    Bisacchi, Gregory S; Manchester, John I

    2015-01-01

    The introduction into clinical practice of an ATPase inhibitor of bacterial DNA gyrase and topoisomerase IV (topo IV) would represent a new-class agent for the treatment of resistant bacterial infections. Novobiocin, the only historical member of this class, established the clinical proof of concept for this novel mechanism during the late 1950s, but its use declined rapidly and it was eventually withdrawn from the market. Despite significant and prolonged effort across the biopharmaceutical industry to develop other agents of this class, novobiocin remains the only ATPase inhibitor of gyrase and topo IV ever to progress beyond Phase I. In this review, we analyze the historical attempts to discover and develop agents within this class and highlight factors that might have hindered those efforts. Within the last 15 years, however, our technical understanding of the molecular details of the inhibition of the gyrase and topo IV ATPases, the factors governing resistance development to such inhibitors, and our knowledge of the physical properties required for robust clinical drug candidates have all matured to the point wherein the industry may now address this mechanism of action with greater confidence. The antibacterial spectrum within this class has recently been extended to begin to include serious Gram negative pathogens such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. In spite of this recent technical progress, adverse economics associated with antibacterial R&D over the last 20 years has diminished industry's ability to commit the resources and perseverance needed to bring new-class agents to launch. Consequently, a number of recent efforts in the ATPase class have been derailed by organizational rather than scientific factors. Nevertheless, within this context we discuss the unique opportunity for the development of ATPase inhibitors of gyrase and topo IV as new-class antibacterial agents with broad spectrum potential. PMID

  15. 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

  16. Quinolone-resistant Campylobacter Infections: Risk Factors and Clinical Consequences1

    PubMed Central

    Neimann, Jakob; Nielsen, Eva Møller; Aarestrup, Frank Møller; Fussing, Vivian

    2004-01-01

    We integrated data on quinolone and macrolide susceptibility patterns with epidemiologic and typing data from Campylobacter jejuni and C. coli infections in two Danish counties. The mean duration of illness was longer for 86 patients with quinolone-resistant C. jejuni infections (median 13.2 days) than for 381 patients with quinolone-sensitive C. jejuni infections (median 10.3 days, p = 0.001). Foreign travel, eating fresh poultry other than chicken and turkey, and swimming were associated with increased risk for quinolone-resistant C. jejuni infection. Eating fresh chicken (of presumably Danish origin) was associated with a decreased risk. Typing data showed an association between strains from retail food products and broiler chickens and quinolone-sensitive domestically acquired C. jejuni infections. An association between treatment with a fluoroquinolone before stool-specimen collection and having a quinolone-resistant C. jejuni infection was not observed. PMID:15207057

  17. 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

  18. 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

  19. [Fibrin-collagen substance as a vehicle for local application of antibacterial agents].

    PubMed

    Gorskiĭ, V A; Gertsog, A A; Leonenko, I V; Shamanek, T P; Sokov, B N

    2002-01-01

    Inhibitory activity of fibrin-collagen substance (FCS) impregnated by various antibacterial agents against various microorganisms was investigated. It was demonstrated that antibacterials bind well with FCS, providing its sufficient antibacterial activity. Determination of growth-inhibition zones showed that antibacterial agents diffuse into medium well and demonstrated the same activity as discs with antibiotics. For clinical practice it is recommended to use for impregnation the following drugs: gentamycin, meropenem, cefriaxone and ciprofloxacin. PMID:12422648

  20. 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

  1. Safety Concerns Surrounding Quinolone Use in Children.

    PubMed

    Patel, Karisma; Goldman, Jennifer L

    2016-09-01

    Fluoroquinolones are highly effective antibiotics with many desirable pharmacokinetic and pharmacodynamic properties including high bioavailability, large volume of distribution, and a broad spectrum of antimicrobial activity. Despite their attractive profile as anti-infective agents, their use in children is limited, primarily due to safety concerns. In this review we highlight the pharmacological properties of fluoroquinolones and describe their current use in pediatrics. In addition, we provide a comprehensive assessment of the safety data associated with fluoroquinolone use in children. Although permanent or destructive arthropathy remains a significant concern, currently available data demonstrate that arthralgia and arthropathy are relatively uncommon in children and resolve following cessation of fluoroquinolone exposure without resulting in long-term sequelae. The concern for safety and risk of adverse events associated with pediatric fluoroquinolone use is likely driving the limited prescribing of this drug class in pediatrics. However, in adults, fluoroquinolones are the most commonly prescribed broad-spectrum antibiotics, resulting in the development of drug-resistant bacteria that can be challenging to treat effectively. The consequence of misuse and overuse of fluoroquinolones leading to drug resistance is a greater, but frequently overlooked, safety concern that applies to both children and adults and one that should be considered at the point of prescribing. PMID:26865283

  2. Synthesis, characterization, and antibacterial activities of novel sulfonamides derived through condensation of amino group containing drugs, amino acids, and their analogs.

    PubMed

    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, (1)HNMR, and (13)CNMR). 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

  3. 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

  4. Differential Distribution of Plasmid-Mediated Quinolone Resistance Genes in Clinical Enterobacteria with Unusual Phenotypes of Quinolone Susceptibility from Argentina

    PubMed Central

    Andres, Patricia; Lucero, Celeste; Soler-Bistué, Alfonso; Guerriero, Leonor; Albornoz, Ezequiel; Tran, Tung; Zorreguieta, Angeles; Galas, Marcelo; Corso, Alejandra; Tolmasky, Marcelo E.

    2013-01-01

    We studied a collection of 105 clinical enterobacteria with unusual phenotypes of quinolone susceptibility to analyze the occurrence of plasmid-mediated quinolone resistance (PMQR) and oqx genes and their implications for quinolone susceptibility. The oqxA and oqxB genes were found in 31/34 (91%) Klebsiella pneumoniae and 1/3 Klebsiella oxytoca isolates. However, the oqxA- and oqxB-harboring isolates lacking other known quinolone resistance determinants showed wide ranges of susceptibility to nalidixic acid and ciprofloxacin. Sixty of the 105 isolates (57%) harbored at least one PMQR gene [qnrB19, qnrB10, qnrB2, qnrB1, qnrS1, or aac(6′)-Ib-cr)], belong to 8 enterobacterial species, and were disseminated throughout the country, and most of them were categorized as susceptible by the current clinical quinolone susceptibility breakpoints. We developed a disk diffusion-based method to improve the phenotypic detection of aac(6′)-Ib-cr. The most common PMQR genes in our collection [qnrB19, qnrB10, and aac(6′)-Ib-cr] were differentially distributed among enterobacterial species, and two different epidemiological settings were evident. First, the species associated with community-acquired infections (Salmonella spp. and Escherichia coli) mainly harbored qnrB19 (a unique PMQR gene) located in small ColE1-type plasmids that might constitute its natural reservoirs. qnrB19 was not associated with an extended-spectrum β-lactamase phenotype. Second, the species associated with hospital-acquired infections (Enterobacter spp., Klebsiella spp., and Serratia marcescens) mainly harbored qnrB10 in ISCR1-containing class 1 integrons that may also have aac(6′)-Ib-cr as a cassette within the variable region. These two PMQR genes were strongly associated with an extended-spectrum β-lactamase phenotype. Therefore, this differential distribution of PMQR genes is strongly influenced by their linkage or lack of linkage to integrons. PMID:23478955

  5. 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

  6. 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

  7. Effective antibacterials: at what cost? The economics of antibacterial resistance and its control.

    PubMed

    White, Anthony R

    2011-09-01

    The original and successful business model of return on investment being sufficiently attractive to the pharmaceutical industry to encourage development of new antibacterial molecules and related diagnostics has been compromised by increasing development costs and regulatory hurdles, resulting in a decreasing chance of success and financial return. The supply of new effective agents is diminishing along with the number of companies engaged in antibacterial research and development. The BSAC Working Party on The Urgent Need:Regenerating Antibacterial Drug Discovery and Development identified the need to establish, communicate and apply the true health and economic value of antibacterials, along with the adoption of meaningful incentives, as part of the future model for antibacterial development. Robust data are needed on the cost of resistance and ineffective treatment of bacterial infection, along with national and local holistic analyses of the cost-benefit of antibacterials. An understanding of the true health and economic value of antibacterials and the cost of resistance across healthcare systems needs to be generated, communicated and used in order to set a pricing and reimbursement structure that is commensurate with value. The development and economic model of antibacterial use needs to be rebuilt based on this value through dialogue with the various stakeholders, including the pharmaceutical industry, and alternative incentives from 'push' to 'pull' and funding models, such as public/private partnerships, agreed. A research and development model that succeeds in developing and delivering new antibacterial agents that address the health needs of society from start to finish, 'from cradle to grave', must be established. PMID:21700625

  8. 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

  9. In vitro and in vivo activities of QA-241, a new tricyclic quinolone derivative.

    PubMed Central

    Asahara, M; Tsuji, A; Goto, S; Masuda, K; Kiuchi, A

    1989-01-01

    The in vitro susceptibilities of 1,310 clinical isolates to QA-241, a novel tricyclic quinolone, were evaluated in comparison with susceptibilities to norfloxacin, ofloxacin, enoxacin, and ciprofloxacin. The MICs of QA-241 for 90% of staphylococci, Enterococcus faecalis isolates, and streptococcal species ranged from 1.56 to 6.25 micrograms/ml, and the activity of QA-241 was similar to those of norfloxacin and enoxacin but two to four times less potent than those of ofloxacin and ciprofloxacin. At the concentration of less than or equal to 1.56 micrograms/ml, QA-241 inhibited 90% of Haemophilus influenzae, Bordetella pertussis, Neisseria gonorrhoeae, and gram-negative enteric bacteria except for Serratia marcescens and Citrobacter freundii. QA-241 was moderately active (MIC for 90% of strains tested, 6.25 to 12.5 micrograms/ml) against S. marcescens, Pseudomonas aeruginosa, Xanthomonas maltophilia, and Bacteroides fragilis. The antibacterial activity of QA-241 was roughly comparable to that of enoxacin but two to four times less potent than that of ofloxacin. In systemic infections in mice with gram-positive cocci and gram-negative rods, the efficacy of QA-241 was generally greater than that of norfloxacin and similar to those of ofloxacin and ciprofloxacin. In urinary tract infections in mice with Escherichia coli or Pseudomonas aeruginosa, QA-241 was as active as ofloxacin and more active than norfloxacin but less active than ciprofloxacin. In pulmonary infections in mice with Klebsiella pneumoniae, the effectiveness of QA-241 was similar to that of ofloxacin. PMID:2679369

  10. 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

  11. Mechanisms involved in quinolone resistance in Mycoplasma mycoides subsp. capri.

    PubMed

    Antunes, Nuno T; Assunção, Patrícia; Poveda, José B; Tavío, María M

    2015-06-01

    Mycoplasma mycoides subsp. capri is a causative agent of contagious agalactia in goats. In this study, M. mycoides subsp. capri mutants were selected for resistance to fluoroquinolones (norfloxacin, enrofloxacin and ciprofloxacin) by serial passes in broth with increasing concentrations of antibiotic. Mutations conferring cross-resistance to the three fluoroquinolones were found in the quinolone resistance determining regions of the four genes encoding DNA gyrase and topoisomerase IV. Different mutations in the DNA gyrase GyrA subunit suggest a different mechanism of inhibition between norfloxacin and the other tested fluoroquinolones. The presence of an adenosine triphosphate-dependent efflux system was suggested through the use of the inhibitor orthovanadate. PMID:25951987

  12. [Investigation of plasmid-mediated quinolone resistance in Escherichia coli strains].

    PubMed

    Aktepe, Orhan Cem; Aşık, Gülşah; Cetinkol, Yeliz; Biçmen, Meral; Gülay, Zeynep

    2012-01-01

    Quinolones are widely used antimicrobial agents, particularly for the treatment of infections caused by gram-negative bacilli such as E.coli. As a consequence, quinolone resistance has been increasing among this species in recent years. Bacterial resistance to quinolones usually results from mutations in the chromosomal genes which encode topoisomerases and also the expression of efflux pumps and loss of porines contributed to development of quinolone resistance. However, recent studies have shown that the spread and increase of quinolone resistance may be due to the transfer of plasmid-mediated genes. To date, three groups of plasmid-mediated quinolone resistance genes, namely qnr, aac(6')-Ib-cr, and qepA, have been described. The aim of this study was to investigate the presence of plasmid-mediated quinolone resistance genes in E.coli clinical isolates. A total of 112 quinolone-resistant E.coli strains isolated from different clinical specimens (84 urine, 16 blood, 10 wound, 2 bronchoalveolar lavage) of which 78 (69.6%) were extended-spectrum beta-lactamase (ESBL) positive, in Afyon Kocatepe University Hospital, Microbiology Laboratory were included in the study. In the isolates, qnrA, qnrB, qnrS, qnrC, qepA, and aac(6')-1b-cr plasmid genes were analysed by polymerase chain reaction (PCR). After aac(6')- 1b determinant was amplified by PCR, all aac(6')-1b positive amplicons were analyzed by digestion with BseGI restriction enzyme to identify aac(6')-1b-cr variant. It was found that, none of the strains horboured qnrA, qnrB, qnrS, qnrC and qepA genes, however, plasmid-mediated quinolone resistance gene aac(6')-1b-cr was found positive in 59.8% (67/112) of the strains. It was notable that 86.6% (58/67) of those isolates were ESBL producers. The rates of quinolone resistance among E.coli isolates infections were high in our region and an increasing trend has been observed in recent years. Our data indicated that the presence of plasmid- mediated resistance genes

  13. Synthesis and antibacterial evaluation of macrocyclic diarylheptanoid derivatives.

    PubMed

    Lin, Hao; Bruhn, David F; Maddox, Marcus M; Singh, Aman P; Lee, Richard E; Sun, Dianqing

    2016-08-15

    Bacterial infections, caused by Mycobacterium tuberculosis and other problematic bacterial pathogens, continue to pose a significant threat to global public health. As such, new chemotype antibacterial agents are desperately needed to fuel and strengthen the antibacterial drug discovery and development pipeline. As part of our antibacterial research program to develop natural product-inspired new antibacterial agents, here we report synthesis, antibacterial evaluation, and structure-activity relationship studies of an extended chemical library of macrocyclic diarylheptanoids with diverse amine, amide, urea, and sulfonamide functionalities. Results of this study have produced macrocyclic geranylamine and 4-fluorophenethylamine substituted derivatives, exhibiting moderate to good activity against M. tuberculosis and selected Gram-positive bacterial pathogens. PMID:27406794

  14. 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

  15. A Theoretical-Experimental Study on the Structure and Activity of Certain Quinolones and the Interaction of Their Cu(II)-Complexes on a DNA Model

    PubMed Central

    Robles, J.; Martín-Polo, J.; Álvarez-Valtierra, L.; Hinojosa, L.

    2000-01-01

    Theoretical electronic Structure methods have been employed to study the structure and activity of certain (free) quinolones and the interaction of their Cu(II)-complexes on a DNA model (Rhodamine 6G (rhod)). As a manner of assessing the generated geometries, the nalidixic acid geometrical parameters obtained were tested against the crystallographic ones and it was found that the average error in the calculated geometries is small. The present study allows us to (1) Rationalize the observed differences in antibiotic activities through their electronic hardnesses. (2) Suggest a plausible mechanism of action for these drugs through formation of a reactive intermediate (or carrier) which would consist of a quinolone anion coordinated to an adequate metal center (Cu(II) in this study). (3) We find that, through this model of DNA (modeled with rhod) the interaction seems to be mediated by an effective π-π stacking. (4) Finally, an in vitro experiment was designed so that the intercalation process in DNA could be experimentally modeled as well. The quenching of the rhod fluorescence is proportional to the strength of the Cu(II)-complex-rhod interaction and therefore provides a quantitative measurement of the “intercalating” capacity of the quinolones and their copper complexes. These results agree well with the theoretical total adduct formation energies. PMID:18475962

  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. Should quinolones come first in Helicobacter pylori therapy?

    PubMed Central

    Berning, Marco; Krasz, Susanne; Miehlke, Stephan

    2011-01-01

    New generations of fluoroquinolones, like levofloxacin and moxifloxacin, exhibit a broad-spectrum activity against Gram-positive and Gram-negative bacteria, and have been successfully introduced into the treatment of Helicobacter pylori infection. Based on a large body of evidence, current guidelines recommend the use of levofloxacin- or moxifloxacin-containing proton-pump inhibitor (PPI) triple therapies in second-line or rescue treatment of H. pylori infection. The efficacy of standard PPI triple therapies has substantially declined during the last decade, mainly due to increasing resistance against the key antibiotics clarithromycin and metronidazole. Therefore, alternative strategies for first-line therapy of H. pylori infection have been evaluated in a considerable number of clinical trials including sequential regimens, nonbismuth quadruple regimens, and quinolone-containing PPI triple therapy regimens. The aim of this paper is to summarize the current body of evidence of levofloxacin- and moxifloxacin-containing regimens in first-line treatment of H. pylori infection, and to discuss the risks and benefits of these strategies in the light of increasing resistance of H. pylori to quinolones. PMID:21694812

  18. Broilers as a source of quinolone-resistant and extraintestinal pathogenic Escherichia coli in the Czech Republic.

    PubMed

    Literak, Ivan; Reitschmied, Tomas; Bujnakova, Dobroslava; Dolejska, Monika; Cizek, Alois; Bardon, Jan; Pokludova, Lucie; Alexa, Pavel; Halova, Dana; Jamborova, Ivana

    2013-02-01

    Extraintestinal Escherichia coli infections are associated with extraintestinal pathogenic E. coli (ExPEC) strains. A total of 114 E. coli isolates were characterized regarding their antimicrobial resistance in a prospective study of 319 broilers from 12 slaughterhouses in the Czech Republic, a European Union member, during 2008. PCR-based assays to define ExPEC-associated traits were performed in resistant strains. Consumption of antimicrobial drugs by poultry in the Czech Republic was also analyzed. Antibiotic resistance was detected in 82% of isolates. Resistance to nalidixic acid and ciprofloxacin was predominant. Plasmid-mediated quinolone resistance genes, qnrB19 and qnrS1, were detected in 1 and 3 of 93 resistant isolates, respectively. Twenty-three percent of resistant isolates were considered as ExPEC. In total, 972 kg of flumequine, enrofloxacin, and difloxacin were used in poultry in the Czech Republic during 2008. High prevalence of broilers with ciprofloxacin-resistant E. coli isolates was linked to consumption of quinolones in poultry. Broilers may comprise an important vehicle for community-wide dissemination of fluoroquinolone-resistant E. coli and ExPEC. Withdrawal of fluoroquinolones from use in chicken production should be seriously considered in the Czech Republic and the European Union as well. PMID:23020862

  19. Computational Study of Quinolone Derivatives to Improve their Therapeutic Index as Anti-malaria Agents: QSAR and QSTR.

    PubMed

    Iman, Maryam; Davood, Asghar; Khamesipour, Ali

    2015-01-01

    Malaria is a parasitic disease caused by five different species of Plasmodium. More than 40% of the world's population is at risk and malaria annual incidence is estimated to be more than two hundred million, malaria is one of the most important public health problems especially in children of the poorest parts of the world, annual mortality is about 1 million. The epidemiological status of the disease justifies to search for control measures, new therapeutic options and development of an effective vaccine. Chemotherapy options in malaria are limited, moreover, drug resistant rate is high. In spite of global efforts to develop an effective vaccine yet there is no vaccine available. In the current study, a series of quinolone derivatives were subjected to quantitative structure activity relationship (QSAR) and quantitative structure toxicity relationship (QSTR) analyses to identify the ideal physicochemical characteristics of potential anti-malaria activity and less cytotoxicity. Quinolone with desirable properties was built using HyperChem program, and conformational studies were performed through the semi-empirical method followed by the PM3 force field. Multi linear regression (MLR) was used as a chemo metric tool for quantitative structure activity relationship modeling and the developed models were shown to be statistically significant according to the validation parameters. The obtained QSAR model reveals that the descriptors PJI2, Mv, PCR, nBM, and VAR mainly affect the anti-malaria activity and descriptors MSD, MAXDP, and X1sol affect the cytotoxicity of the series of ligands. PMID:26330866

  20. Computational Study of Quinolone Derivatives to Improve their Therapeutic Index as Anti-malaria Agents: QSAR and QSTR

    PubMed Central

    Iman, Maryam; Davood, Asghar; Khamesipour, Ali

    2015-01-01

    Malaria is a parasitic disease caused by five different species of Plasmodium. More than 40% of the world’s population is at risk and malaria annual incidence is estimated to be more than two hundred million, malaria is one of the most important public health problems especially in children of the poorest parts of the world, annual mortality is about 1 million. The epidemiological status of the disease justifies to search for control measures, new therapeutic options and development of an effective vaccine. Chemotherapy options in malaria are limited, moreover, drug resistant rate is high. In spite of global efforts to develop an effective vaccine yet there is no vaccine available. In the current study, a series of quinolone derivatives were subjected to quantitative structure activity relationship (QSAR) and quantitative structure toxicity relationship (QSTR) analyses to identify the ideal physicochemical characteristics of potential anti-malaria activity and less cytotoxicity. Quinolone with desirable properties was built using HyperChem program, and conformational studies were performed through the semi-empirical method followed by the PM3 force field. Multi linear regression (MLR) was used as a chemo metric tool for quantitative structure activity relationship modeling and the developed models were shown to be statistically significant according to the validation parameters. The obtained QSAR model reveals that the descriptors PJI2, Mv, PCR, nBM, and VAR mainly affect the anti-malaria activity and descriptors MSD, MAXDP, and X1sol affect the cytotoxicity of the series of ligands. PMID:26330866

  1. 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

  2. Antibacterial activity of local herbs collected from Murree (Pakistan) against multi-drug resistant Klebsiella pneumonae, E. coli and methyciline resistant Staphylococcus aureus.

    PubMed

    Mansoor, Qaisar; Shaheen, Saira; Javed, Uzma; Shaheen, Uzma; Iqrar, Irum; Ismail, Muhammad

    2013-07-01

    Exploring healing power in plants emerged in prehistory of human civilization. Sustaining good health has been achieved over the millions of years by use of plant products in various traditional sockets. A major contribution of medicinal plants to health care systems is their limitless possession of bioactive components that stimulate explicit physiological actions. Luckily Pakistan is blessed with huge reservoir of plants with medicinal potential and some of them; we focused in this study for their medicinal importance.In this study we checked the antibacterial activity inherent in Ricinus communis, Solanum nigrum, Dodonaea viscose and Berberis lyceum extracts for multidrug resistance bacterial strains Klebsiella pneumonae, E. coli and methyciline resistant Staphylococcus aureus. MRSA showed sensitivity for Ricinus communis. Multidrug resistant Klebsiella pneumonae was sensitive with Pine roxburgii and Ricinus communis but weakly susceptible for Solanum nigrum. Multidrug resistant E. coli was resistant to all plant extracts. Treatment of severe infections caused by the bacterial strains used in this study with Ricinus communis, Pine roxburgii and Solanum nigrum can lower the undesired side effects of synthetic medicine and also reduce the economic burden. PMID:23811466

  3. Determinants of Quinolone versus Trimethoprim-Sulfamethoxazole Use for Outpatient Urinary Tract Infection

    PubMed Central

    Stuck, Anna K.; Täuber, Martin G.; Schabel, Maria; Lehmann, Thomas; Suter, Herbert

    2012-01-01

    Quinolones are increasingly favored over trimethoprim-sulfamethoxazole (TMP-SMX) for empirical treatment of uncomplicated urinary tract infection (UTI). This is associated with increasing resistance toward this broad-spectrum group of antibiotics. Our objective is to describe the prescribing patterns and identify determinants of the choice between TMP-SMX and quinolones for outpatient UTI treatment in Switzerland. An ongoing national Sentinel surveillance system was used to study 11,799 antibiotic prescriptions for UTI in adult outpatients and associated physician and patient factors between 2006 and 2008, to compare the prescription of quinolones versus that of TMP-SMX for treatment of UTI. Most UTI episodes were diagnosed as cystitis (90%). TMP-SMX was prescribed for one-fifth (22%) of UTIs. Independent predictors for prescribing quinolones were pyelonephritis and physicians with low thresholds for prescribing antibiotics for upper respiratory tract infections (“high prescribers”), whereas female patients were more likely to receive TMP-SMX. High-prescribing physicians also more often cared for patients who themselves favor antibiotic treatment (P < 0.001). Quinolones are commonly prescribed to outpatients with UTI. Nonclinical factors influence the choice of quinolones versus TMP-SMX, which may provide opportunities for interventions to improve prescribing patterns and control quinolone resistance. PMID:22232276

  4. Antibacterial properties of nanoparticles.

    PubMed

    Hajipour, Mohammad J; Fromm, Katharina M; Ashkarran, Ali Akbar; Jimenez de Aberasturi, Dorleta; de Larramendi, Idoia Ruiz; Rojo, Teofilo; Serpooshan, Vahid; Parak, Wolfgang J; Mahmoudi, Morteza

    2012-10-01

    Antibacterial agents are very important in the textile industry, water disinfection, medicine, and food packaging. Organic compounds used for disinfection have some disadvantages, including toxicity to the human body, therefore, the interest in inorganic disinfectants such as metal oxide nanoparticles (NPs) is increasing. This review focuses on the properties and applications of inorganic nanostructured materials and their surface modifications, with good antimicrobial activity. Such improved antibacterial agents locally destroy bacteria, without being toxic to the surrounding tissue. We also provide an overview of opportunities and risks of using NPs as antibacterial agents. In particular, we discuss the role of different NP materials. PMID:22884769

  5. 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.

  6. Antibacterial activities of the methanol extracts of Canarium schweinfurthii and four other Cameroonian dietary plants against multi-drug resistant Gram-negative bacteria.

    PubMed

    Dzotam, Joachim K; Touani, Francesco K; Kuete, Victor

    2016-09-01

    Bacterial infections are among the major cause of morbidity and mortality worldwide. The present study was designed to evaluate the in vitro antibacterial activities of the methanol extracts of five Cameroonian edible plants namely Colocasia esculenta, Triumfetta pentandra, Hibiscus esculentus, Canarium schweinfurthii and Annona muricata against a panel of 19 multidrug resistant Gram-negative bacterial strains. The liquid broth microdilution was used to determine the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of the extracts. The preliminary phytochemical screening of the extracts was conducted according to the standard phytochemical methods. Results showed that all extracts contained compounds belonging to the classes of polyphenols, triterpenes and steroids, other classes of chemicals being selectively distributed. Canarium schweinfurthii extract showed the best activity with MIC values ranging from 64 to 1024 μg/mL against 89.5% of the 19 tested bacteria strains. MIC values below or equal to 1024 μg/mL were also recorded with Triumfetta pentandra, Annona muricata, Colocasia esculenta and Hibiscus esculentus extracts respectively against 15/19 (78.9%), 11/19 (57.9%), 10/19 (52.6%) and 10/19 (52.6%) tested bacteria. Extract from C. schweinfurthii displayed the lowest MIC value (64 μg/mL) against Escherichia coli AG100ATet. Finally, the results of this work provide baseline information for the use of C. esculenta, T. pentandra, H. esculentus, C. schweinfurthii and A. muricata in the treatment of bacterial infections including multidrug resistant phenotypes. PMID:27579004

  7. 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

  8. [Antibacterial activity of cefpodoxime against clinical isolates in 2000 and 2001].

    PubMed

    Abe, Tomomi; Fukuoka, Takashi; Sato, Yuki; Ito, Kazuyoshi; Sei, Masami

    2002-12-01

    As the post-marketing surveillance of cefpodoxime proxetil (Banan), MICs of cefpodoxime (CPDX, an active form of Banan) against 1090 clinical isolates of 22 species from 15 medical institutions all over Japan from June 2000 to March 2001 were measured using the broth microdilution method approved by the Japanese Society of Chemotherapy and compared with those of oral cephem antibacterials, cefaclor, cefdinir, cefditoren, and cefcapene. In this study, remarkable change in the activity of CPDX was observed in Streptococcus pneumoniae and Haemophilus influenzae compared with the susceptibility in the studies before Banan was launched. This cause is considered to be the increase in the incidence of the following resistant strains: penicillin-intermediate S. pneumoniae (47.3%), penicillin-resistant S. pneumoniae (PRSP, 15.1%), and beta-lactamase-negative ampicillin-resistant (BLNAR) H. influenzae (24.0%), which were scarcely isolated in 1989 when Banan was launched. Other tested drugs also exhibited low activity against these resistant strains. However, CPDX showed comparatively good activity with MIC90 of 2 micrograms/mL against PRSP. Against methicillin-susceptible Staphylococcus spp., Streptococcus pyogenes, Streptococcus agalactiae, and Moraxella catarrhalis, CPDX also showed comparatively good activity with MIC90 of < or = 4 micrograms/mL, which was almost equal to that in the studies before its marketing. Against quinolones-resistant Neisseria gonorrhoeae, CPDX showed excellent activity with MIC90 of 0.5 microgram/mL. Against members of the family Enterobacteriaceae except for Citrobacter freundii, Enterobacter spp., Proteus vulgaris, and Morganella morganii, CPDX showed good activity. However, in Escherichia coli, Klebsiella spp. Proteus spp., and Providencia spp., there are some high-resistant strains to all tested drugs including CPDX. Against Peptostreptococcus spp., MIC90 of CPDX was 8 micrograms/mL and its MIC range was widely distributed from 0.03 to 32

  9. Combination of hollow fiber liquid phase microextraction followed by HPLC-DAD and multivariate curve resolution to determine antibacterial residues in foods of animal origin.

    PubMed

    Tajabadi, Fateme; Ghambarian, Mahnaz; Yamini, Yadollah; Yazdanfar, Najmeh

    2016-11-01

    In the present research, a carrier mediated hollow fiber based liquid-phase microextraction approach (HF-LPME) prior to high performance liquid chromatography-diode array detection (HPLC-DAD) was developed for the simultaneous determination of the antibacterial residues of four tetracyclines (TCs) and five quinolones (QNs), which are commonly used as veterinary medicines. In order to obtain high extraction efficiency, the parameters affecting HF-LPME were optimized using a three-factor and three-level Box-Behnken design under response surface methodology. This method was validated according to the recommendations of the Food and Drug Administration (FDA), and, for the first time, successfully applied to a wide range of animal source food samples such as fish, milk, and honey as well as the liver and muscles of lamb and chicken. Analytical performance was determined in terms of linearity, intra- and inter-assay precision, detection and quantification limits, matrix effect, accuracy, and drug stability in real samples. Detection and quantitation limits for the different antibiotics ranged between 0.5-20ngg(-1) and 1.25-40ngg(-1), respectively. Intra and inter-day repeatability, expressed as the relative standard deviation, were in the ranges of 3.4-10.7% and 5.0-11.5%, respectively. The procedure allows good preconcentration factors of 175-700. The results of the validation process proved that the method is suitable for determining TCs and QNs residues in surveillance programs. Finally, the applicability of the proposed method was successfully confirmed by the extraction and determination of nine antibiotics in various animal source food samples. The importance of this methodology relies on the combination of HF-LPME/HPLC-DAD second-order data with multivariate curve resolution-alternative least squares (MCR-ALS) algorithm, which improves the resolution of some overlapped chromatograms and, hence, increases the accuracy and repeatability of drug determination. PMID

  10. 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