\\u000a This synopsis of published literature summarises data on the in vitro antibacterial activity and pharmacodynamics of fluoroquinolones.\\u000a Data were compiled for ciprofloxacin, levofloxcin, moxifloxacin, gatifloxacin, grepafloxacin, gemifloxacin, trovafloxacin,\\u000a sitafloxacin and garenoxacin. All of these quinolones are almost equipotent against gram-negative bacteria but demonstrate\\u000a improved activity against gram-positive species. The new quinolones are uniformly active against gram-positive species except\\u000a Streptococcus
A. Dalhoff; F.-J. Schmitz
Moxifloxacin (Bay 12-8039) is a new 8 methoxy quinolone antibacterial. The MIC90 values are < or = 0.25 mg/l for Streptococcus pneumoniae (irrespective of penicillin susceptibility), Haemophilus influenzae (beta-lactamase positive or negative), Morexella catarrhalis, Bordetella pertussis, Legionella sp., Mycoplasma pneumoniae, Clamydia pneumoniae, Mycobacterium tuberculosis, methicillin-sensitive Staphylococcus aureus, beta-haemolytic streptococci (macrolide-sensitive or -resistant), Listeria sp., most Enterobacteriaceae, Salmonella sp., Shigella sp., Neisseria gonorrhoeae, N. menigitidis, Pasteurella spp., Vibrio spp. and Yersinia enterocolitica. For Mycobacterium intracellularae, methicillin-resistant S. aureus (MRSA), ciprofloxacin-resistant S. aureus, Citrobacter freundii, Providencia sp., Serratia sp., P. aeruginosa and other non-fermentive Gram-negative rods, MIC90s are in the range 0.5-4 mg/l. For anaerobic bacteria species, MIC90s are also in the range 0.25-4 mg/l. Moxifloxacin is bactericidal at concentrations 2- to 4-fold higher than the MIC and is rapidly bactericidal against most common pathogen groups at concentrations achieved in serum with a 400 mg dose that is between 0.5-4 mg/l. There is a post-antibiotic effect against Gram-positive and -negative bacteria. Resistant mutants are at present difficult to select in the laboratory but in general, moxifloxacin has poorer activity against strains resistant to ciprofloxacin compared to those which are susceptible. Animal and laboratory pharmacodynamic models indicate that the MIC and area under the serum concentration time curve predict outcome. Various animal models mainly of respiratory tract infection indicate equivalent or superior results compared to existing or other developmental agents. Human pharmacokinetics in healthy volunteers indicate linear pharmacokinetics over the dose range 50-800 mg/day. A single dose of 400 mg produces a maximum serum concentration of 2.5-4.5 mg/l, half-life of 11-15 h, AUC of 25-40 mg x h/l and volume of distribution of 2.5-3.5 L/kg. Protein binding is about 50% and two metabolites have been identified (M-1 and M-2). Bioavailability is > 85% and a minority of clearance is via the kidneys. No dose modification is required in renal impairment. Extra vascular penetration, where studied, is comparable to that of other quinolones. At present undergoing clinical trials, with a focus on respiratory tract infection, it is likely that moxifloxacin will provide effective therapy for pathogens with MICs of < or = 0.25-0.5 mg/l. The safety profile in a large number of human subjects is awaited. PMID:15992072
MacGowan, A P
The objective of this study was to compare protonation equilibrium and lipophilicity of two quinolone antibacterials, grepafloxacin (GPFX) and ciprofloxacin (CPFX), in order to give an insight into effects on the physicochemical properties by slight structural motifs. The protonation equilibrium was investigated by a spectrophotometry. Macro- and micro-dissociation constants were simultaneously determined, based on nonlinear regression analysis using the MULTI
Jin Sun; Shigeko Sakai; Yoshihiko Tauchi; Yoshiharu Deguchi; Jimin Chen; Ruhua Zhang; Kazuhiro Morimoto
It was shown that (fluoro)quinolone antibiotics form strongly fluorescent solid-state complexes with Eu(III) and Tb(III) lanthanide ions, with a wavelength red-shift beneficial for applications to greenhouse-cover polymers. Complexes with optimal properties were prepared by the mechanical activation of fine-dispersed composite mixtures with the lanthanide salts. The spectral properties, photo-stability to UV-light, and compatibility with the polyethylene matrix were investigated. The
A. V. Polishchuk; E. T. Karaseva; T. Korpela; V. E. Karasev
The mutagenic potential of 12 quinolone antibacterial agents (quinolones) was examined at concentrations of 3.91-1000 ng/plate with or without S9 mix in Escherichia coli WP2uvrA/pKM101. All quinolones showed mutagenic potential in the strain: the maximum numbers of revertant colonies were observed at 7.81 ng/plate for clinafloxacin and sitafloxacin; 15.63 ng/plate for ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin; and 31.25-500 ng/plate for enoxacin, lomefloxacin, norfloxacin and ofloxacin. The numbers for all quinolones were comparable between the groups with and without S9 mix. In all quinolones, bactericidal effects were observed at one or two higher concentrations than their mutagenic concentrations except for enoxacin without S9 mix. From these results, the WP2uvrA/pKM101 strain is proved to be highly sensitive to quinolones. PMID:16171969
Hayasaki, Yayoi; Itoh, Satoru; Kato, Michiyuki; Furuhama, Kazuhisa
The mutagenic potential of 12 quinolone antibacterial agents (quinolones) was examined at concentrations of 3.91–1000ng\\/plate with or without S9 mix in Escherichia coli WP2uvrA\\/pKM101. All quinolones showed mutagenic potential in the strain: the maximum numbers of revertant colonies were observed at 7.81ng\\/plate for clinafloxacin and sitafloxacin; 15.63ng\\/plate for ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin; and 31.25–500ng\\/plate for enoxacin, lomefloxacin,
Yayoi Hayasaki; Satoru Itoh; Michiyuki Kato; Kazuhisa Furuhama
The photochemical clastogenic potential of 12 quinolone antibacterial agents with or without light irradiation was assessed by an in vitro chromosomal aberration test using cultured CHL cells. Exposure to all test compounds, except for DK-507k, increased the incidence of cells with structural aberrations excluding gap (TA) following light irradiation. Test compounds used in the present study under light irradiation were
Satoru Itoh; Shiho Nakayama; Hiroyasu Shimada
The general pharmacological properties of (-)-(S)-9-fluoro-2,3-dihydro-3- methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1,4] benzoxazine-6-carboxylic acid hemihydrate (levofloxacin, DR-3355, CAS 100986-85-4), an optically active isomer of ofloxacin, were examined. 1. Central nervous system (CNS): DR-3355 at 200-600 mg/kg p.o. showed depressant activity on the CNS, as was indicated by the depressant syndrome (mice), decreased spontaneous motor activity (mice) and hypothermia (mice and rabbits). In the cat behavior and EEG experiments, it had both stimulant and depressant effects at 30-100 mg/kg i.p., and caused transient slow waves followed by seizures at 20-30 mg/kg i.v. DR-3355 had no effect on convulsion, hexobarbital anesthesia, pain reaction to a tail pinch, or conditioned avoidance response, except that it showed mild analgesic activity in acetic acid writhing at 600 mg/kg p.o. 2. Respiratory and cardiovascular system: DR-3355 produced a hypotensive and a bradycardiac effect after the rapid i.v. injection of 6 mg/kg or more in anesthetized dogs, accompanied by an increase in plasma histamine concentration. Both changes were markedly reduced when the test drug was administered by continuous i.v. infusion. 3. Autonomic nervous system: DR-3355 inhibited nictitating membrane contraction induced by both pre- and post-ganglionic stimulation, and inhibited the depressor response to acetylcholine at 20 mg/kg i.v. It had no influence on pupil size or on pressor response to norepinephrine. 4. Gastrointestinal system: DR-3355 at 600 mg/kg p.o. inhibited gastric secretion. Dog gastrointestinal motility was slightly inhibited, and was then stimulated over the dose range of 2-20 mg/kg i.v. It had no influence on gastrointestinal propulsion, the gastric emptying rate or the gastric mucosa. 5. Isolated smooth muscle: At a concentration of 5 x 10(-4) g/ml, DR-3355 was devoid of spasmogenic or smasmolytic activity, except for showing a slight relaxation effect (trachea), inhibition of nicotine-induced contraction (ileum) and spontaneous or oxytocin-induced motility (pregnant uterus). 6. Miscellaneous: DR-3355 inhibited the urine output and carrageenin-induced paw edema at 600 mg/kg p.o. It had no effect on skeletal muscle contraction or the corneal reflex. PMID:1622443
Takasuna, K; Kasai, Y; Usui, C; Takahashi, M; Hirohashi, M; Tamura, K; Takayama, S
New validated cellular targets are needed to reinvigorate antibacterial drug discovery. This need could potentially be filled by riboswitches—messenger RNA (mRNA) structures that regulate gene expression in bacteria. Riboswitches are unique among RNAs that serve as drug targets in that they have evolved to form structured and highly selective receptors for small drug-like metabolites. In most cases, metabolite binding to
Kenneth F Blount; Ronald R Breaker
The antibacterial activity of DQ-113, formerly D61-1113, was compared with those of antibacterial agents currently available. MICs at which 90% of the isolates tested are inhibited (MIC90s) of DQ-113 against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus and methicillin-susceptible and -resistant coagulase-negative staphylococci were 0.03, 0.008, 0.03, and 0.06 ?g/ml, respectively. Moreover, DQ-113 showed the most potent activity against ofloxacin-resistant and methicillin-resistant S. aureus, with a MIC90 of 0.25?g/ml. DQ-113 inhibited the growth of all strains of Streptococcus pneumoniae, including penicillin-resistant strains, and Streptococcus pyogenes at 0.06 ?g/ml, and DQ-113 was more active than the other quinolones tested against Enterococcus faecalis and Enterococcus faecium with MIC90s of 0.25 and 2 ?g/ml, respectively. Against vancomycin-resistant enterococci, DQ-113 showed the highest activity among the reference compounds, with a MIC range from 0.25 to 2 ?g/ml. DQ-113 also showed a potent activity against Haemophilus influenzae, including ampicillin-resistant strains (MIC90, 0.015 ?g/ml), and Moraxella catarrhalis (MIC90, 0.03 ?g/ml). The activity of DQ-113 was roughly comparable to that of levofloxacin against all species of Enterobacteriaceae. The MICs of DQ-113 against ofloxacin-susceptible Pseudomonas aeruginosa ranged from 0.25 to 2 ?g/ml, which were four times higher than those of ciprofloxacin. From these results, DQ-113 showed the most potent activity against gram-positive pathogens among antibacterial agents tested.
Tanaka, Mayumi; Yamazaki, Emi; Chiba, Megumi; Yoshihara, Kiyomi; Akasaka, Takaaki; Takemura, Makoto; Sato, Kenichi
We examined whether household use of antibacterial cleaning and hygiene products is an emerging risk factor for carriage of antimicrobial drug-resistant bacteria on hands of household members. Households (N = 224) were random- ized to use of antibacterial or nonantibacterial cleaning and hygiene products for 1 year. Logistic regression was used to assess the influence of antibacterial product use in
Allison E. Aiello; Bonnie Marshall; Stuart B. Levy; Phyllis Della-Latta; Susan X. Lin; Elaine Larson
Sensitivity of 6 F. tularensis strains to 57 antibiotics and synthetic antibacterial drugs was studied. It was shown that the strains were highly sensitive to aminoglycosides, tetracyclines, anzamycins, quinolones, chloramphenicol, nitrofurantoin, nitroxoline, novobiocin and fusidin and resistant to penicillins, cephalosporins, polypeptides, vancomycin and sulfanylamides. The interrace differences in F. tularensis could be detected only by sensitivity to erythromycin, oleandomycin and spiramycin. There was observed no cross resistance to streptomycin and other aminoglycosides in F. tularensis. Assay of F. tularensis sensitivity to antibacterial drugs of various groups with the rapid photometric procedure and the agar diffusion method revealed that the results were highly comparable. PMID:2610533
Vasi'lev, N T; Oborin, V A; Vasi'lev, P G; Glushkova, O V; Kravets, I D; Levchuk, B A
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 21(st) century have also been reviewed in the present article. PMID:23776832
Rai, Jaswant; Randhawa, Gurpreet Kaur; Kaur, Mandeep
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.
Rai, Jaswant; Randhawa, Gurpreet Kaur; Kaur, Mandeep
Genome studies suggest that DNA gyrase is the sole type II topoisomerase and likely the unique target of quinolones in Mycobacterium tuberculosis. Despite the emerging importance of quinolones in the treatment of mycobacterial disease, the slow growth and high pathogenicity of M. tuberculosis have precluded direct purification of its gyrase and detailed analysis of quinolone action. To address these issues, we separately overexpressed the M. tuberculosis DNA gyrase GyrA and GyrB subunits as His-tagged proteins in Escherichia coli from pET plasmids carrying gyrA and gyrB genes. The soluble 97-kDa GyrA and 72-kDa GyrB subunits were purified by nickel chelate chromatography and shown to reconstitute an ATP-dependent DNA supercoiling activity. The drug concentration that inhibited DNA supercoiling by 50% (IC(50)) was measured for 22 different quinolones, and values ranged from 2 to 3 microg/ml (sparfloxacin, sitafloxacin, clinafloxacin, and gatifloxacin) to >1,000 microg/ml (pipemidic acid and nalidixic acid). By comparison, MICs measured against M. tuberculosis ranged from 0.12 microg/ml (for gatifloxacin) to 128 microg/ml (both pipemidic acid and nalidixic acid) and correlated well with the gyrase IC(50)s (R(2) = 0.9). Quinolones promoted gyrase-mediated cleavage of plasmid pBR322 DNA due to stabilization of the cleavage complex, which is thought to be the lethal lesion. Surprisingly, the measured concentrations of drug inducing 50% plasmid linearization correlated less well with the MICs (R(2) = 0.7). These findings suggest that the DNA supercoiling inhibition assay may be a useful screening test in identifying quinolones with promising activity against M. tuberculosis. The quinolone structure-activity relationship demonstrated here shows that C-8, the C-7 ring, the C-6 fluorine, and the N-1 cyclopropyl substituents are desirable structural features in targeting M. tuberculosis gyrase. PMID:15047530
Aubry, Alexandra; Pan, Xiao-Su; Fisher, L Mark; Jarlier, Vincent; Cambau, Emmanuelle
Genome studies suggest that DNA gyrase is the sole type II topoisomerase and likely the unique target of quinolones in Mycobacterium tuberculosis. Despite the emerging importance of quinolones in the treatment of mycobacterial disease, the slow growth and high pathogenicity of M. tuberculosis have precluded direct purification of its gyrase and detailed analysis of quinolone action. To address these issues, we separately overexpressed the M. tuberculosis DNA gyrase GyrA and GyrB subunits as His-tagged proteins in Escherichia coli from pET plasmids carrying gyrA and gyrB genes. The soluble 97-kDa GyrA and 72-kDa GyrB subunits were purified by nickel chelate chromatography and shown to reconstitute an ATP-dependent DNA supercoiling activity. The drug concentration that inhibited DNA supercoiling by 50% (IC50) was measured for 22 different quinolones, and values ranged from 2 to 3 ?g/ml (sparfloxacin, sitafloxacin, clinafloxacin, and gatifloxacin) to >1,000 ?g/ml (pipemidic acid and nalidixic acid). By comparison, MICs measured against M. tuberculosis ranged from 0.12 ?g/ml (for gatifloxacin) to 128 ?g/ml (both pipemidic acid and nalidixic acid) and correlated well with the gyrase IC50s (R2 = 0.9). Quinolones promoted gyrase-mediated cleavage of plasmid pBR322 DNA due to stabilization of the cleavage complex, which is thought to be the lethal lesion. Surprisingly, the measured concentrations of drug inducing 50% plasmid linearization correlated less well with the MICs (R2 = 0.7). These findings suggest that the DNA supercoiling inhibition assay may be a useful screening test in identifying quinolones with promising activity against M. tuberculosis. The quinolone structure-activity relationship demonstrated here shows that C-8, the C-7 ring, the C-6 fluorine, and the N-1 cyclopropyl substituents are desirable structural features in targeting M. tuberculosis gyrase.
Aubry, Alexandra; Pan, Xiao-Su; Fisher, L. Mark; Jarlier, Vincent; Cambau, Emmanuelle
The phototoxic potentials of quinolone derivatives and the possibility of free radical contribution to their phototoxicity were investigated by measuring increments in ear thickness. Balb/c mice, fasted overnight, were orally administered ofloxacin (OFLX), lomefloxacin (LMFX), enoxacin (ENX), ciprofloxacin (CPFX) and DR-3355 (the s-isomer of OFLX), and immediately exposed to ultraviolet-A light (UVA: 320-400 nm) for 4 h (21.6 joules/cm2). Measurement of ear thickness was carried out 0, 24 and 48 h after the end of irradiation. The time-course profiles of ear thickness varied with both the doses and the quinolone used, but linear dose-response curves were obtained from the data 24 h after irradiation ended. The 50% ear thickness increment-inducing doses of LMFX, ENX, OFLX, CPFX and DR-3355 were calculated as 24.8, 81.9, 428.0, 457.9 and 526.6 mg/kg, respectively. The phototoxic potential of these quinolones coincided with the data obtained previously by measuring the incidence of erythema on the ears. Pretreatment with butylated hydroxtoluene, a free radical scavenger, almost completely prevented all swelling reactions induced by the quinolones. These results suggest that the degree of phototoxicity induced by the quinolones used could depend on the balance between the generation of free radicals and the effectiveness of the defense systems against toxic radicals. PMID:1949080
Wagai, N; Tawara, K
We examined whether household use of antibacterial cleaning and hygiene products is an emerging risk factor for carriage of antimicrobial drug–resistant bacteria on hands of household members. Households (N = 224) were randomized to use of antibacterial or nonantibacterial cleaning and hygiene products for 1 year. Logistic regression was used to assess the influence of antibacterial product use in homes. Antibacterial product use did not lead to a significant increase in antimicrobial drug resistance after 1 year (odds ratio 1.33, 95% confidence interval 0.74–2.41), nor did it have an effect on bacterial susceptibility to triclosan. However, more extensive and longer term use of triclosan might provide a suitable environment for emergence of resistant species. Further research on this issue is needed.
Marshall, Bonnie; Levy, Stuart B.; Della-Latta, Phyllis; Lin, Susan X.; Larson, Elaine
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.
Devasahayam, Gina; Scheld, W. Michael; Hoffman, Paul S.
The in vitro activities of DX-619, des-fluoro(6) quinolone, against 1,208 clinical isolates were examined. DX-619 was particularly potent against staphylococci, including ciprofloxacin- and methicillin-resistant strains; the MIC at which 90% of the strains tested were inhibited was 0.5 ?g/ml. In addition, DX-619 was also active against gram-negative bacteria.
Fujikawa, Katsuko; Chiba, Megumi; Tanaka, Mayumi; Sato, Kenichi
The antibacterial activity of DQ-113, formerly D61-1113, was compared with those of antibacterial agents currently available. MICs at which 90% of the isolates tested are inhibited (MIC90s) of DQ-113 against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus and methicillin-susceptible and -resis- tant coagulase-negative staphylococci were 0.03, 0.008, 0.03, and 0.06 g\\/ml, respectively. Moreover, DQ-113 showed the most potent activity
Mayumi Tanaka; Emi Yamazaki; Megumi Chiba; Kiyomi Yoshihara; Takaaki Akasaka; Makoto Takemura; Kenichi Sato
To gain further insight into the structural requirements of the aliphatic group at position 2 for their antimycobacterial activity, some N-alkyl-4-(1H)-quinolones bearing position 2 alkynyls with various chain length and triple bond positions were prepared and tested for in vitro antibacterial activity against rapidly-growing strains of mycobacteria, the vaccine strain Mycobacterium bovis BCG, and methicillin-resistant Staphylococcus aureus strains, EMRSA-15 and -16. The compounds were also evaluated for inhibition of ATP-dependent MurE ligase of Mycobacterium tuberculosis. The lowest MIC value of 0.5 mg/L (1.2-1.5 ?M) was found against M. fortuitum and M. smegmatis. These compounds displayed no or only weak toxicity to the human lung fibroblast cell line MRC-5 at 100 ?M concentration. The quinolone derivatives exhibited pronounced activity against the epidemic MRSA strains (EMRSA-15 and -16) with MIC values of 2-128 mg/L (5.3-364.7 ?M), and M. bovis BCG with an MIC value of 25 mg/L (66.0-77.4 ?M). In addition, the compounds inhibited the MurE ligase of M. tuberculosis with moderate to weak activity showing IC50 values of 200-774 ?M. The increased selectivity towards mycobacterial bacilli with reference to MRC-5 cells observed for 2-alkynyl quinolones compared to their corresponding 2-alkenyl analogues serves to highlight the mycobacterial specific effect of the triple bond. Exploration of a terminal bromine atom at the side chain of N-alkyl-2-(E)-alkenyl-4-(1H)-quinolones showed improved antimycobacterial activity whereas a cyclopropyl residue at N-1 was suggested to be detrimental to antibacterial activity.
Wube, Abraham; Guzman, Juan-David; Hufner, Antje; Hochfellner, Christina; Blunder, Martina; Bauer, Rudolf; Gibbons, Simon; Bhakta, Sanjib; Bucar, Franz
... species); Differences in physical characteristics of humans compared to various animal species (eg, weight); Antibacterial ... More results from www.fda.gov/drugs/drugsafety/informationbydrugclass
We have determined and quantified spectrophotometrically the capacity of producing reactive oxygen species (ROS) as 1O2 during the photolysis with UV-A light of 5 new synthesized naphthyl ester derivates of well-known quinolone antibacterials (nalidixic acid (1), cinoxacin (2), norfloxacin (3), ciprofloxacin (4) and enoxacin (5)). The ability of the naphthyl ester derivatives (6–10) to generate singlet oxygen were detecting and for the first time quantified by the histidine assay, a sensitive, fast and inexpensive method. The following tendency of generation of singlet oxygen was observed: compounds 7 > 10 > 6 > 8 > 9 >> parent drugs 1–5.
Zoltan, Tamara; Vargas, Franklin; Izzo, Carla
We examined drug concentrations and the incidence of retinal degeneration in the eyes of albino BALB\\/c mice after a single intravenous administration of sitafloxacin plus a 4 h period of UVA irradiation. Retinal degeneration was induced at 40 mg\\/kg or more plus UVA irradiation, and there was little decrease in ocular sitafloxacin concentration under UVA irradiation. We then examined the
Kohji Shimoda; Satoshi Okawara; Michiyuki Kato
We compared the phototoxic potential of the quinolone antibac- terial agent sitafloxacin with those of lomefloxacin and sparfloxa- cin. Female BALB\\/c mice were given a single intravenous admin- istration of sitafloxacin, lomefloxacin, or sparfloxacin at 10 or 40 mg\\/kg, followed by ultraviolet-A (UVA) irradiation for 4 h (21.6 J\\/cm 2 ). At 10 mg\\/kg, all quinolones induced either none or
Kohji Shimoda; Toshiko Ikeda; Satoshi Okawara; Michiyuki Kato
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.
This study is the first of its type to evaluate sources, patterns and appropriateness of antibacterial drug consumption within the Jordanian population. It uses a structured random interview to customers arriving at community pharmacy stores seeking antibacterial medication for systemic infections. Dispensed antibacterial drugs belonged to eight different main classes of systemically used antibacterial drugs in accordance with the Anatomical
Amal G. Al-Bakri; Yasser Bustanji; Al-Motassem Yousef
While the resistance of bacteria to traditional antibiotics is a major public health concern, the use of extremely potent antibacterial agents is limited by their lack of selectivity. As in cancer therapy, antibacterial targeted therapy could provide an opportunity to reintroduce toxic substances to the antibacterial arsenal. A desirable targeted antibacterial agent should combine binding specificity, a large drug payload per binding event, and a programmed drug release mechanism. Recently, we presented a novel application of filamentous bacteriophages as targeted drug carriers that could partially inhibit the growth of Staphylococcus aureus bacteria. This partial success was due to limitations of drug-loading capacity that resulted from the hydrophobicity of the drug. Here we present a novel drug conjugation chemistry which is based on connecting hydrophobic drugs to the phage via aminoglycoside antibiotics that serve as solubility-enhancing branched linkers. This new formulation allowed a significantly larger drug-carrying capacity of the phages, resulting in a drastic improvement in their performance as targeted drug-carrying nanoparticles. As an example for a potential systemic use for potent agents that are limited for topical use, we present antibody-targeted phage nanoparticles that carry a large payload of the hemolytic antibiotic chloramphenicol connected through the aminoglycoside neomycin. We demonstrate complete growth inhibition toward the pathogens Staphylococcus aureus, Streptococcus pyogenes, and Escherichia coli with an improvement in potency by a factor of ?20,000 compared to the free drug.
Yacoby, Iftach; Bar, Hagit; Benhar, Itai
Crystal structures of hydrochlorides of 7-chloro- and 7-methyl-4-iminecinnoline analogs of antibacterial quinolones have been determined by X-ray diffraction methods. The cell parameters for the 7-chloro (1) analog in the space group P21\\/c are a = 9.061(1), b = 19.062(1), c = 7.310(1)Ĺ, ? = 104.92(1)°, Z = 4, and Dcalc = 1.569 g\\/cm3 and for the 7-methyl (2) analog in
Marek L. G?ówka; Dariusz Martynowski; Alina Napieraj; Andrzej Olczak; Andrzej Sta?czak; Zbigniew Ochocki; Wies?awa Lewgowd
The pneumococcal chromosome encodes about 140 transporters, many of which are predicted to be involved in efflux. In order to critically evaluate pneumococcal efflux, a series of transporter mutants were constructed, and their phenotypes were assayed by disk diffusion, microdilution drug susceptibility testing (MIC testing), growth of cultures at sub-MIC concentrations, and phenotype microarray analysis. Mutants with mutations in seven ATP binding cassette (ABC) transporters, three multiantimicrobial extrusion (MATE) family efflux pumps, and one major facilitator superfamily (MFS) transporter were obtained in Streptococcus pneumoniae strain DP1004. The susceptibility of these 11 mutants to over 250 different substances was compared to that of the parent strain. Of the tested transporters, only the ABC transporter PatAB (SP2073-5) presented a clear multidrug resistance (MDR) profile, as the mutant showed significantly increased susceptibility to ethidium bromide, acriflavine, and berberine. Among the other transporters analyzed, the mutants devoid of the MATE efflux pump SP2065 exhibited reduced susceptibility to novobiocin, and those with mutations of the MATE family DinF transport system (SP1939) exhibited increased susceptibility to moxifloxacin, ciprofloxacin, and levofloxacin. This change in quinolone MIC was found to be independent from the competence-mediated effect of quinolones on the cinA-recA-dinF operon. Furthermore, the dinF mutant, in contrast to the parental strain, allowed selection for quinolone-resistant mutants when exposed to moxifloxacin. These data confirm the clear MDR profile of the PatAB ABC transporter and suggest for the MATE DinF a phenotype associated with quinolone susceptibility, particularly for moxifloxacin. PMID:23114782
Tocci, Nadia; Iannelli, Francesco; Bidossi, Alessandro; Ciusa, Maria Laura; Decorosi, Francesca; Viti, Carlo; Pozzi, Gianni; Ricci, Susanna; Oggioni, Marco Rinaldo
The pneumococcal chromosome encodes about 140 transporters, many of which are predicted to be involved in efflux. In order to critically evaluate pneumococcal efflux, a series of transporter mutants were constructed, and their phenotypes were assayed by disk diffusion, microdilution drug susceptibility testing (MIC testing), growth of cultures at sub-MIC concentrations, and phenotype microarray analysis. Mutants with mutations in seven ATP binding cassette (ABC) transporters, three multiantimicrobial extrusion (MATE) family efflux pumps, and one major facilitator superfamily (MFS) transporter were obtained in Streptococcus pneumoniae strain DP1004. The susceptibility of these 11 mutants to over 250 different substances was compared to that of the parent strain. Of the tested transporters, only the ABC transporter PatAB (SP2073-5) presented a clear multidrug resistance (MDR) profile, as the mutant showed significantly increased susceptibility to ethidium bromide, acriflavine, and berberine. Among the other transporters analyzed, the mutants devoid of the MATE efflux pump SP2065 exhibited reduced susceptibility to novobiocin, and those with mutations of the MATE family DinF transport system (SP1939) exhibited increased susceptibility to moxifloxacin, ciprofloxacin, and levofloxacin. This change in quinolone MIC was found to be independent from the competence-mediated effect of quinolones on the cinA-recA-dinF operon. Furthermore, the dinF mutant, in contrast to the parental strain, allowed selection for quinolone-resistant mutants when exposed to moxifloxacin. These data confirm the clear MDR profile of the PatAB ABC transporter and suggest for the MATE DinF a phenotype associated with quinolone susceptibility, particularly for moxifloxacin.
Tocci, Nadia; Iannelli, Francesco; Bidossi, Alessandro; Ciusa, Maria Laura; Decorosi, Francesca; Viti, Carlo; Pozzi, Gianni; Ricci, Susanna
: The usage of veterinary antibacterial drugs in dogs and cats in Sweden and Norway for the period 1990–1998 was investigated by use of drug wholesalers' statistics. Additionally, usage of human antibacterial drugs in these species in Sweden was investigated by use of prescription data for the period 1996–1998. On average, more than 50% of the prescribed veterinary antibacterials in
K. Odensvik; K. Grave; C. Greko
The cephalosporin class antibacterial agent, cefazolin, was intercalated into layered double hydroxides (LDHs) in order to improve the drug efficiency as well as to achieve the controlled release property. Cefazolin molecules were incorporated into LDH through conventional ion exchange reaction. X-ray diffraction pattern analyses confirmed that cefazolin molecules were intercalated between the interlayer spaces of LDH. Fourier-transform infrared spectra and
Seung-Jin Ryu; Hyun Jung; Jae-Min Oh; Jin-Kyu Lee; Jin-Ho Choy
Quinolones are a class of antibacterial agents for the treatment of several infectious diseases (e.g. urinary and respiratory tract infections). They are used worldwide due to their broad spectrum of activity, high bioavailability and good safety profile. The safety profile varies from quinolone to quinolone. The aim of this article was to review the neurological and psychiatric adverse drug reaction (ADR) profile of quinolones, using a literature search strategy designed to identify case reports and case series. A literature search using PubMed/MEDLINE (from inception to 31 October 2010) was performed to identify case reports and case series related to quinolone-associated neurological and psychiatric ADRs. The search was conducted in two phases: the first phase was the literature search and in the second phase relevant articles were identified through review of the references of the selected articles. Relevant articles were defined as articles referring to adverse events/reactions associated with the use of any quinolone. Abstracts referring to animal studies, clinical trials and observational studies were excluded. Identified case reports were analysed by age group, sex, active substances, dosage, concomitant medication, ambulatory or hospital-based event and seriousness, after Medical Dictionary for Regulatory Activities (MedDRA®) coding. From a total of 828 articles, 83 were identified as referring to nervous system and/or psychiatric disorders induced by quinolones. 145 individual case reports were extracted from the 83 articles. 40.7% of the individual case reports belonged to psychiatric disorders only, whereas 46.9% related to neurological disorders only. Eight (5.5%) individual case reports presented both neurological and psychiatric ADRs. Ciprofloxacin, ofloxacin and pefloxacin were the quinolones with more neurological and psychiatric ADRs reported in the literature. Ciprofloxacin has been extensively used worldwide, which may explain the higher number of reports, while for ofloxacin and pefloxacin, the number of reports may be over-representative. A total of 232 ADRs were identified from the selected articles, with 206 of these related to psychiatric and/or neurological ADRs. The other 26 were related to other body systems but were reported together with the reactions of interest. Mania, insomnia, acute psychosis and delirium were the most frequently reported psychiatric adverse events; grand mal convulsion, confusional state, convulsions and myoclonus were the most frequently reported neurological adverse events. Several aspects should be taken into account in the development of CNS adverse effects, such as the pharmacokinetics of quinolones, chemical structure and quinolone uptake in the brain. These events may affect not only susceptible patients but also 'healthy' patients. PMID:21585220
Tomé, Ana M; Filipe, Augusto
Regulatory agencies play a critical role in the licensing of new antimicrobial agents. To address the pivotal role played by regulatory agencies, particularly in the context of a paucity of new drugs active against bacteria resistant to currently available drugs, the BSAC formed the 'Urgent Need' Working Party to address the regeneration of antibacterial drug discovery and development. The Working Party identified a number of issues, including: increased application of pharmacokinetic/pharmacodynamic principles to expedite drug development; the need to prioritize licensing of drugs (including 'orphan' drugs) active in life-threatening infections; and expansion of the use of surrogate markers and rapid point of care diagnostics to facilitate drug development. PMID:21700629
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.
Onodera, Yoshikuni; Chiba, Megumi; Hoshino, Kazuki; Gotoh, Naomasa
Background One of the major issues in the fight against infectious diseases is the notable increase in multiple drug resistance in pathogenic species. For that reason, newly acquired high-throughput data on virulent microbial agents attract the attention of many researchers seeking potential new drug targets. Many approaches have been used to evaluate proteins from infectious pathogens, including, but not limited to, similarity analysis, reverse docking, statistical 3D structure analysis, machine learning, topological properties of interaction networks or a combination of the aforementioned methods. From a biological perspective, most essential proteins (knockout lethal for bacteria) or highly conserved proteins (broad spectrum activity) are potential drug targets. Ribosomal proteins comprise such an example. Many of them are well-known drug targets in bacteria. It is intuitive that we should learn from nature how to design good drugs. Firstly, known antibiotics are mainly originating from natural products of microorganisms targeting other microorganisms. Secondly, paleontological data suggests that antibiotics have been used by microorganisms for million years. Thus, we have hypothesized that good drug targets are evolutionary constrained and are subject of evolutionary selection. This means that mutations in such proteins are deleterious and removed by selection, which makes them less susceptible to random development of resistance. Analysis of the speed of evolution seems to be good approach to test this hypothesis. Results In this study we show that pN/pS ratio of genes coding for known drug targets is significantly lower than the genome average and also lower than that for essential genes identified by experimental methods. Similar results are observed in the case of dN/dS analysis. Both analyzes suggest that drug targets tend to evolve slowly and that the rate of evolution is a better predictor of drugability than essentiality. Conclusions Evolutionary rate can be used to score and find potential drug targets. The results presented here may become a useful addition to a repertoire of drug target prediction methods. As a proof of concept, we analyzed GO enrichment among the slowest evolving genes. These may become the starting point in the search for antibiotics with a novel mechanism.
Pharmacokinetic-pharmacodynamic (PKPD) modeling and simulation has evolved as an important tool for rational drug development and drug use, where developed models characterize both the typical trends in the data and quantify the variability in relationships between dose, concentration, and desired effects and side effects. In parallel, rapid emergence of antibiotic-resistant bacteria imposes new challenges on modern health care. Models that can characterize bacterial growth, bacterial killing by antibiotics and immune system, and selection of resistance can provide valuable information on the interactions between antibiotics, bacteria, and host. Simulations from developed models allow for outcome predictions of untested scenarios, improved study designs, and optimized dosing regimens. Today, much quantitative information on antibiotic PKPD is thrown away by summarizing data into variables with limited possibilities for extrapolation to different dosing regimens and study populations. In vitro studies allow for flexible study designs and valuable information on time courses of antibiotic drug action. Such experiments have formed the basis for development of a variety of PKPD models that primarily differ in how antibiotic drug exposure induces amplification of resistant bacteria. The models have shown promise for efficacy predictions in patients, but few PKPD models describe time courses of antibiotic drug effects in animals and patients. We promote more extensive use of modeling and simulation to speed up development of new antibiotics and promising antibiotic drug combinations. This review summarizes the value of PKPD modeling and provides an overview of the characteristics of available PKPD models of antibiotics based on in vitro, animal, and patient data. PMID:23803529
Nielsen, Elisabet I; Friberg, Lena E
For many years, DNA gyrase was thought to be responsible both for unlinking replicated daughter chromosomes and for controlling negative superhelical tension in bacterial DNA. However, in 1990 a homolog of gyrase, topoisomerase IV, that had a potent decatenating activity was discovered. It is now clear that topoisomerase IV, rather than gyrase, is responsible for decatenation of interlinked chromosomes. Moreover, topoisomerase IV is a target of the 4-quinolones, antibacterial agents that had previously been thought to target only gyrase. The key event in quinolone action is reversible trapping of gyrase-DNA and topoisomerase IV-DNA complexes. Complex formation with gyrase is followed by a rapid, reversible inhibition of DNA synthesis, cessation of growth, and induction of the SOS response. At higher drug concentrations, cell death occurs as double-strand DNA breaks are released from trapped gyrase and/or topoisomerase IV complexes. Repair of quinolone-induced DNA damage occurs largely via recombination pathways. In many gram-negative bacteria, resistance to moderate levels of quinolone arises from mutation of the gyrase A protein and resistance to high levels of quinolone arises from mutation of a second gyrase and/or topoisomerase IV site. For some gram-positive bacteria, the situation is reversed: primary resistance occurs through changes in topoisomerase IV while gyrase changes give additional resistance. Gyrase is also trapped on DNA by lethal gene products of certain large, low-copy-number plasmids. Thus, quinolone-topoisomerase biology is providing a model for understanding aspects of host-parasite interactions and providing ways to investigate manipulation of the bacterial chromosome by topoisomerases.
Drlica, K; Zhao, X
DNA topoisomerases comprise a major aspect of basic cellular biology and are molecular targets for a variety of drugs like antibiotics, antibacterials and anticancer drugs. They act by inhibiting the topoisomerase molecule from relegating DNA strands after cleavage and convert the topoisomerases molecule into a DNA damaging agent. Though drugs of various categories acting through different mechanisms are available for the treatment, there are still problems associated with the currently available drugs. Therefore, Structural biologists, Structural chemists and Medicinal chemists all around the world have been identifying, designing, synthesizing and evaluating a variety of novel bioactive molecules targeting topoisomerase. This review summarizes types of topoisomerase and drug treating each class along with their structural requirement and activity. The emphasis has been laid in particular on the new potential heterocyles and the possible treatments as well as the current ongoing research status in the field of topoisomerase as dual targeting. PMID:22380774
Kathiravan, Muthu K; Khilare, Madhavi M; Nikoomanesh, Kiana; Chothe, Aparna S; Jain, Kishor S
Bacteriophages have been used for more than a century for (unconventional) therapy of bacterial infections, for half a century as tools in genetic research, for 2 decades as tools for discovery of specific target-binding proteins, and for nearly a decade as tools for vaccination or as gene delivery vehicles. Here we present a novel application of filamentous bacteriophages (phages) as targeted drug carriers for the eradication of (pathogenic) bacteria. The phages are genetically modified to display a targeting moiety on their surface and are used to deliver a large payload of a cytotoxic drug to the target bacteria. The drug is linked to the phages by means of chemical conjugation through a labile linker subject to controlled release. In the conjugated state, the drug is in fact a prodrug devoid of cytotoxic activity and is activated following its dissociation from the phage at the target site in a temporally and spatially controlled manner. Our model target was Staphylococcus aureus, and the model drug was the antibiotic chloramphenicol. We demonstrated the potential of using filamentous phages as universal drug carriers for targetable cells involved in disease. Our approach replaces the selectivity of the drug itself with target selectivity borne by the targeting moiety, which may allow the reintroduction of nonspecific drugs that have thus far been excluded from antibacterial use (because of toxicity or low selectivity). Reintroduction of such drugs into the arsenal of useful tools may help to combat emerging bacterial antibiotic resistance.
Yacoby, Iftach; Shamis, Marina; Bar, Hagit; Shabat, Doron; Benhar, Itai
General pharmacological effects of T-3761, a new oral quinolone antibacterial agent, on the respiratory and cardiovascular systems, autonomic nervous system and other functions were investigated in laboratory animals. The results obtained are summarized as follows. 1. Respiratory and cardiovascular systems: Oral administration of T-3761 at doses of 100-1,000 mg/kg did not affect in conscious rats. But intravenous administration of T-3761 at doses of 10-100 mg/kg caused an increase in respiratory rate, induced hypotension, caused increase or decrease in heart rate and altered ECG patterns (elevation of T waves and reduction of voltage of QRS complexes, etc.) in anesthetized dogs. Intravenous administration of T-3761 at doses of 10-100 mg/kg showed respiratory rate increase or decrease, hypertension, heart rate decrease and ECG patterns changes (T waves elevation and extrasystole) in anesthetized rabbits. 2. Autonomic nervous system and smooth muscle organs: T-3761 increased the epinephrine-induced contraction of the isolated guinea pig vas deferens at concentration of 10(-5)-10(-4) g/ml. T-3761 decreased the acetylcholine-induced contraction of the isolated guinea pig ileum and epinephrine-induced relaxation of the isolated guinea pig trachea-chain at concentration of 10(-4) g/ml. T-3761 increased the norepinephrine-induced contraction of the isolated rabbit thoracic aorta at concentration of 10(-4) g/ml. Oral administration of T-3761 at a dose of 1,000 mg/kg exerted slight mydriasis in mice. 3. Digestive system: T-3761 decreased the spontaneous motilities of isolated ileum and colon at concentration of 10(-4) g/ml. Oral administration of T-3761 at a dose of 1,000 mg/kg inhibited gastric output and intestinal transit time in rats or mice. 4. Renal functions: Oral administration of T-3761 at a dose of 300 mg/kg increased Na+ excretion but did not affect PSP excretion in rats. 5. Hematological examinations: T-3761 showed no effects on resistance to hemolysis, blood coagulation and platelet aggregation in rabbits at concentration of 10(-6)-10(-4) g/ml. Oral administration of T-3761 at dose of 100-1,000 mg/kg did not affect bleeding time or blood glucose level in rats. 6. Miscellaneous effects: Intravenous administration of T-3761 at a dose of 100 mg/kg slightly inhibited the twitch tension of gastrocnemius in anesthetized rats. Oral administration of T-3761 at doses of 300-1,000 mg/kg exerted slight augmentation of carrageenin-induced hind paw edema in rats. From these results, it can be assumed that T-3761 had a wide safety margin as an oral antibacterial agent. PMID:7637205
Furuhata, K; Hiraiwa, T; Terashima, N; Arai, H; Ono, S; Hashiba, K; Maekawa, M; Kitamura, K; Nakada, Y; Mori, Y
Fluoroquinolones are broad-spectrum antimicrobial agents that target type II topoisomerases. Many fluoroquinolones are highly specific for bacterial type II topoisomerases and act against both DNA gyrase and topoisomerase IV. In Escherichia coli, mutations causing quinolone resistance are often found in the gene that encodes the A subunit of DNA gyrase. One common site for resistance-conferring mutations alters Ser83, and mutations to Leu or Trp result in high levels of resistance to fluoroquinolones. In the present study we demonstrate that the mutation of Ser83 to Trp in DNA gyrase (GyrS83W) also results in sensitivity to agents that are potent inhibitors of eukaryotic topoisomerase II but that are normally inactive against prokaryotic enzymes. Epipodophyllotoxins, such as etoposide, teniposide and amino-azatoxin, inhibited the DNA supercoiling activity of GyrS83W, and the enzyme caused elevated levels of DNA cleavage in the presence of these agents. The DNA sequence preference for GyrS83W-induced cleavage sites in the presence of etoposide was similar to that seen with eukaryotic type II topoisomerases. Introduction of the GyrS83W mutation in E. coli strain RFM443-242 by site-directed mutagenesis sensitized it to epipodophyllotoxins and amino-azatoxin. Our results demonstrate that sensitivity to agents that target topoisomerase II is conserved between prokaryotic and eukaryotic enzymes, suggesting that drug interaction domains are also well conserved and likely occur in domains important for the biochemical activities of the enzymes.
Gruger, Thomas; Nitiss, John L.; Maxwell, Anthony; Zechiedrich, E. Lynn; Heisig, Peter; Seeber, Siegfried; Pommier, Yves; Strumberg, Dirk
Diclofenac sodium (Dc) was found to possess antibacterial activity against both drug-sensitive and drug-resistant clinical\\u000a isolates of Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Mycobacterium spp., in addition to its potent anti-inflammatory activity. The time-kill curve study indicates that this non-steroidal drug\\u000a exhibits bactericidal activity against Listeria, E. coli, and M. tuberculosis. The antibacterial activity of Dc comes, in part,
K. Mazumdar; S. G. Dastidar; J. H. Park; N. K. Dutta
Fluoroquinolones are an important class of anti-bacterial s, but as with many anti-infectives, drug-resistance is an increasing problem. Fluoroquinolones inhibit DNA-gyrase, an enzyme, which is able to alter the topology of DNA. However, there is only little structural information. In the literature, there are two rather different proposals for the binding mode of quinolones. Via docking calculations and MD simulations,
Jorn Lenz; Thomas Lemcke; Peter Heisig; Andrew Torda
The total usage of antibacterial and antiparasitic drugs in animals in Sweden between 1988 and 1993 was assessed. The data for the antibacterial drugs were divided among the different classes of drug used each year. Special attention was paid to the use of antibacterial drugs in feeding stuffs and to their use in pigs and fish. During the period studied, the total usage of antibacterial drugs remained stable at approximately 35 tonnes of active substance annually. The use of antibacterial drugs for growth-promoting purposes was prohibited in Sweden in 1986 and became available by veterinary prescription only. As a result the total amount used annually has decreased and stabilised at a level about 35 per cent lower than before the ban. Important changes during 1988 to 1993 were a doubled usage of tetracyclines and a 50 per cent decrease in the use of olaquindox. The five major classes of antibacterial drugs used in 1993 were benzyl penicillin (13.2 tonnes), tetracyclines (8.8 tonnes), olaquindox (3.5 tonnes), sulphonamides (2.0 tonnes) and aminoglycosides (1.9 tonnes). The total annual usage of coccidiostatic drugs, mainly used in the poultry industry, was stable at approximately 10 tonnes, while the usage of other antiparasitic drugs increased slightly to 7.7 tonnes. PMID:8890462
Björnerot, L; Franklin, A; Tysén, E
Traditionally, the in vitro activity of antibacterial agents is characterized by their minimal inhibitory concentrations. However, these endpoints are,\\u000a by nature, discrete and do not provide information on time-dependent killing of the bacteria during the incubation period.\\u000a Nevertheless, the pharmacodynamic characteristics of antibacterial agents are almost always defined by correlating a static\\u000a endpoint describing the antibacterial activity of an agent
K.-J. Schaper; S. Schubert; A. Dalhoff
The purpose of the present study was to develop and characterize the chitosan sponges loading with doxycycline hyclate and their antibacterial activities. The pore density of chitosan sponge prepared with freeze drying technique was increased as the higher concentrated chitosan solution was used. The sponge prepared from 10% w/w of the chitosan solution and crosslinking with glutaraldehyde solution was utilized for loading with doxycycline hyclate. The drug release and sustainable antibacterial activity of fabricated sponge were assessed using dissolution test and agar diffusion test, respectively. Drug release from non-crosslinked sponge into phosphate buffer pH7.4 was slower than that from crosslinked sponge since the former could absorb the medium and form gel to retard the initial drug diffusion. Sustainable antibacterial activity of developed sponge was evident against S. aureus and E. coli. In conclusion, the in vitro release profile and antibacterial efficiency indicated that doxycycline hyclate could be sustained using chitosan sponge.
Drug features that contribute to the activity of quinolones against mammalian topoisomerase II and cultured cells: correlation between enhancement of enzyme-mediated DNA cleavage in vitro and cytotoxic potential.
CP-115,953 [6,8-difluoro-7-(4'-hydroxyphenyl)-1-cyclopropyl-4- quinolone-3-carboxylic acid] is a novel quinolone that is highly active against topoisomerase II in vitro and in mammalian cells in culture (M. J. Robinson, B. A. Martin, T. D. Gootz, P. R. McGuirk, M. Moynihan, J. A. Sutcliffe, and N. Osheroff, J. Biol. Chem. 266:14585-14592, 1991). However, the features of the drug that contribute to its activity towards mammalian systems have not been characterized. Therefore, CP-115,953 and a series of related quinolones were examined for their activity against calf thymus topoisomerase II and cultured mammalian cells. CP-115,953 stimulated DNA cleavage mediated by the type II enzyme with a potency that was approximately 600-fold greater than that of the antimicrobial quinolone ciprofloxacin and approximately 50-fold greater than that of the antineoplastic drug etoposide. As determined by the ability to enhance enzyme-mediated DNA cleavage, quinolone activity towards calf thymus topoisomerase II was enhanced by the presence of a cyclopropyl group at the N-1 ring position and by the presence of a fluorine at C-8. Furthermore, the 4'-hydroxyphenyl substituent at the C-7 position was critical for the potency of CP-115,953 towards the mammalian type II enzyme. In this regard, the aromatic nature of the C-7 ring as well as the presence and the position of the 4'-hydroxyl group contributed greatly to drug activity. Finally, the cytotoxicity of quinolones in the CP-115,953 series towards mammalian cells paralleled the in vitro stimulation of DNA cleavage by topoisomerase II rather than the inhibition of enzyme-catalyzed DNA relaxation. This correlation strongly suggests that these quinolones promote cell death by converting topoisomerase II to a cellular poison.
Elsea, S H; McGuirk, P R; Gootz, T D; Moynihan, M; Osheroff, N
The antibacterial potency of eight anticoccidial drugs was tested in a soil bacteria bioassay (pour plate method), EC50-values between 2.4 and 19.6?M were obtained; however, one compound, nicarbazin exhibited an EC50-value above the maximum tested concentration (21?M, 9.1mgL?1). The potency of mixtures of two of the compounds, narasin and nicarbazin, was synergistic (more than additive) with 10-fold greater antibacterial potency
Martin Hansen; Kristine A. Krogh; Asbjřrn Brandt; Jan H. Christensen; Bent Halling-Sřrensen
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
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 bc(1) 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
Heeb, Stephan; Fletcher, Matthew P; Chhabra, Siri Ram; Diggle, Stephen P; Williams, Paul; Cámara, Miguel
We report the discovery and characterization of a novel ribosome inhibitor (NRI) class that exhibits selective and broad-spectrum antibacterial activity. Compounds in this class inhibit growth of many gram-positive and gram-negative bacteria, including the common respiratory pathogens Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Moraxella catarrhalis, and are nontoxic to human cell lines. The first NRI was discovered in a high-throughput screen designed to identify inhibitors of cell-free translation in extracts from S. pneumoniae. The chemical structure of the NRI class is related to antibacterial quinolones, but, interestingly, the differences in structure are sufficient to completely alter the biochemical and intracellular mechanisms of action. Expression array studies and analysis of NRI-resistant mutants confirm this difference in intracellular mechanism and provide evidence that the NRIs inhibit bacterial protein synthesis by inhibiting ribosomes. Furthermore, compounds in the NRI series appear to inhibit bacterial ribosomes by a new mechanism, because NRI-resistant strains are not cross-resistant to other ribosome inhibitors, such as macrolides, chloramphenicol, tetracycline, aminoglycosides, or oxazolidinones. The NRIs are a promising new antibacterial class with activity against all major drug-resistant respiratory pathogens.
Dandliker, Peter J.; Pratt, Steve D.; Nilius, Angela M.; Black-Schaefer, Candace; Ruan, Xiaoan; Towne, Danli L.; Clark, Richard F.; Englund, Erika E.; Wagner, Rolf; Weitzberg, Moshe; Chovan, Linda E.; Hickman, Robert K.; Daly, Melissa M.; Kakavas, Stephan; Zhong, Ping; Cao, Zhensheng; David, Caroline A.; Xuei, Xiaoling; Lerner, Claude G.; Soni, Niru B.; Bui, Mai; Shen, Linus L.; Cai, Yingna; Merta, Philip J.; Saiki, Anne Y. C.; Beutel, Bruce A.
We report the discovery and characterization of a novel ribosome inhibitor (NRI) class that exhibits selective and broad-spectrum antibacterial activity. Compounds in this class inhibit growth of many gram-positive and gram-negative bacteria, including the common respiratory pathogens Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Moraxella catarrhalis, and are nontoxic to human cell lines. The first NRI was discovered in a high-throughput screen designed to identify inhibitors of cell-free translation in extracts from S. pneumoniae. The chemical structure of the NRI class is related to antibacterial quinolones, but, interestingly, the differences in structure are sufficient to completely alter the biochemical and intracellular mechanisms of action. Expression array studies and analysis of NRI-resistant mutants confirm this difference in intracellular mechanism and provide evidence that the NRIs inhibit bacterial protein synthesis by inhibiting ribosomes. Furthermore, compounds in the NRI series appear to inhibit bacterial ribosomes by a new mechanism, because NRI-resistant strains are not cross-resistant to other ribosome inhibitors, such as macrolides, chloramphenicol, tetracycline, aminoglycosides, or oxazolidinones. The NRIs are a promising new antibacterial class with activity against all major drug-resistant respiratory pathogens. PMID:14638491
Dandliker, Peter J; Pratt, Steve D; Nilius, Angela M; Black-Schaefer, Candace; Ruan, Xiaoan; Towne, Danli L; Clark, Richard F; Englund, Erika E; Wagner, Rolf; Weitzberg, Moshe; Chovan, Linda E; Hickman, Robert K; Daly, Melissa M; Kakavas, Stephan; Zhong, Ping; Cao, Zhensheng; David, Caroline A; Xuei, Xiaoling; Lerner, Claude G; Soni, Niru B; Bui, Mai; Shen, Linus L; Cai, Yingna; Merta, Philip J; Saiki, Anne Y C; Beutel, Bruce A
The appearance of new antibiotic-resistant bacteria is a societal problem that requires the development of new alternative treatments. Therefore, this work evaluated the antibacterial activity of ethanolic (EHI), dichloromethanic (EDI) and hexanic (EHE) extracts from Aristolochia cymbifera stems and the combination of these extracts with an antimicrobial drug to develop a new antibacterial therapy. The EDI, EHE and EHI extracts were obtained by maceration using three different solvents. The minimal inhibitory concentrations (MIC) of these extracts were determined using the microdilution test to determine the antibacterial potential of these extracts and their combination with streptomycin against Staphylococcus aureus, Bacillus cereus, Klebsiella pneumoniae and Shigella flexneri. The extract dose leading to the cytotoxicity of 50% of the cells (CC50) was evaluated using mammalian cells MA104 and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. The extracts had a MIC under 500 mg/L and a CC50 lower than 50 mg/L. The antibiotic/extract proportion influenced the antibacterial activity of the mixtures, and the proportion that optimized the antibacterial activity of streptomycin was a mixture that contained 75 percent of extract. This composition included less than 6.5 mg/L of extract and 2.5 mg/L of streptomycin and has potential as a new antibacterial therapy. PMID:24040585
Silva, Willer F; Cecílio, Samyra G; Magalhăes, Cintia Lb; Ferreira, Jaqueline Ms; Tótola, Antonio H; de Magalhaes, Jose C
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).
Patel, Mohan N.; Dosi, Promise A.; Bhatt, Bhupesh S.; Thakkar, Vasudev R.
The corrosion behavior of aluminium in 2 M HCl solution in the absence and presence of four compounds of antibacterial drug was investigated using hydrogen evolution, weight loss, and potentiostatic polarization techniques. It was found that, the inhibition efficiency of these compounds depends on their concentration and chemical structure. The inhibitive action of these compounds was discussed in terms of
Noninferiority (NI) clinical trials have been used to assess antibacterial drug efficacy in treating nosocomial and ventilator-associated pneumonia. Previously published trials have employed prespecified NI margins of 15% or 20% based on clinical response or microbiological endpoints. However, as those studies do not describe the statistical and clinical considerations underpinning the margins selected, their scientific plausibility cannot be substantiated. In
Alfred Sorbello; Scott Komo; Thamban Valappil
Use of systemic antibacterial drugs in the countries of central and eastern Europe (CCEE) has been studied using the defined daily doses (DDD) methodology. For the comparison, national wholesale data from Bulgaria, the Czech Republic, Estonia, Hungary, Lithuania, Slovakia, Slovenia and Romania for the years 1989 and 1992 were used, i.e. for the years before and after the rapid sociopolitical
R. A. Kiivet; V. Bíba; L. Stika; D. Enache; V. Foltan; J. Gulbinovic; N. Oltványi; A. Orazem; M. Popova
Five novel N-substituted demethylvancomycin derivatives were rationally designed and synthesized by using a structure-based approach. The in vitro antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA), gentamicin-resistant Enterococcus faecalis (GRE), methicillin-resistant Streptococcus pneumoniae (MRS), and vancomycin-resistant Enterococcus faecalis (VRE) were evaluated. One of the compounds, N-(6-phenylheptyl)demethylvancomycin (12 a), was found to exhibit more potent antibacterial activity than vancomycin and demethylvancomycin. Compound 12 a was also found to be ~18-fold more efficacious than vancomycin against MRSA; however, the two compounds were found to have similar efficacy against MRS. Furthermore, compound 12 a exhibited a favorable pharmacokinetic profile with a half-life of 5.11±0.52 h, which is longer than that of vancomycin (4.3±1.9 h). These results suggest that 12 a is a promising antibacterial drug candidate for further preclinical evaluation. PMID:23576378
Chang, Jun; Zhang, Si-Ji; Jiang, Yong-Wei; Xu, Liang; Yu, Jian-Ming; Zhou, Wen-Jiang; Sun, Xun
A human isolate ofSalmonella typhimurium was found to be highly resistant to several antibiotics including quinolones (MIC of ciprofloxacin 16 mg\\/l). Killing by ciprofloxacin was only achieved after prolonged exposure to drug concentrations above the MIC. The quinolone resistance of this particular strain was not mediated by plasmids which, however, coded for several other resistance properties.
H. Hof; I. Ehrhard; H. Tschäpe
This study describes a new drug-loaded coating scaffold applied in infection therapy during bone regeneration. Chitosan (CS) containing antibacterial berberine was coated on a nano-hydroxyapatite/polyamide66 (n-HA/PA66) scaffold to realize bone regeneration together with antimicrobial properties. The porous scaffold was fabricated using the phase-inversion method with a porosity of about 84% and macropore size of 400-600 ?m. The morphology, mechanical properties and drug-release behavior were investigated at different ratios of chitosan to berberine. The results show that the elastic modulus and compressive strength of the coated scaffolds were improved to 35.4 MPa and 1.7 MPa, respectively, about 7 times and 3 times higher than the uncoated scaffolds. After a burst release of berberine within the first 3 h in PBS solution, a continuous berberine release can last 150 h, which is highly dependent on the coating concentration and suitable for antibacterial requirement of orthopaedic surgery. The bactericidal test confirms a strong antibiotic effect of the delivery system and the minimum inhibitory concentration of the drug is 0.02 mg/ml. Moreover, in vitro biological evaluation demonstrates that the coating scaffolds act as a good matrix for MG63 adhesion, crawl, growth and proliferation, suggesting that the antibacterial delivery system has no cytotoxicity. We expect the drug-delivery system to have a potential application in bone regeneration or defect repair. PMID:20566065
Huang, Di; Zuo, Yi; Zou, Qin; Zhang, Li; Li, Jidong; Cheng, Lin; Shen, Juan; Li, Yubao
Text Version... these deliberations and a review of available data for ABS, ABECB, 3 and ABOM, the FDA has not found it possible to define an NI margin for active ... More results from www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation
Antibacterial properties of the Soviet drug nitazol which is a derivative of imidazole were studied. It was shown that nitazol in a dose of 4-8 micrograms/ml was highly active against gram-negative nonsporulating anaerobes, gram-positive anaerobic cocci and spore-forming Clostridia spp. Unlike metronidazole, it was efficient against both standard and clinical strains of facultative anaerobes such as E. coli, S. aureus and Klebsiella spp. isolated from patients with peritonitis and being poly-resistant to antibiotics. It was found in vitro that the antibacterial effect of nitazol was higher when it was used in combination with some antibiotics. It was demonstrated on experimental models of peritonitis caused by Staphylococcus spp. and E. coli in mice that nitazol used alone or in combination with gentamicin had a favourable effect on the animal survival and lifespan. The combination of nitazol with gentamicin was applied in the combined treatment of appendicular peritonitis in 80 children and its high therapeutic efficacy was stated. Nitazol is useful as an antibacterial drug in the combined treatment of children with purulent peritonitis. PMID:2264753
Tsyganenko, A Ia; Topuzov, V S; Kalinichenko, N F; Kovalenko, N I; Davidenko, V B; Gabysheva, L S; Liapunov, N A; Starobinets, Z G; Osolodchenko, T P; Vasil'chenko, V N
In the present article we examine the antiplasmodial activities of novel quinolone derivatives bearing extended alkyl or alkoxy side chains terminated by a trifluoromethyl group. In the series under investigation, the IC50 values ranged from 1.2 to ? 30 nM against chloroquine-sensitive and multidrug-resistant Plasmodium falciparum strains. Modest to significant cross-resistance was noted in evaluation of these haloalkyl- and haloalkoxy-quinolones for activity against the atovaquone-resistant clinical isolate Tm90-C2B, indicating that a primary target for some of these compounds is the parasite cytochrome bc1 complex. Additional evidence to support this biochemical mechanism includes the use of oxygen biosensor plate technology to show that the quinolone derivatives block oxygen consumption by parasitized red blood cells in a fashion similar to atovaquone in side-by-side experiments. Atovaquone is extremely potent and is the only drug in clinical use that targets the Plasmodium bc1 complex, but rapid emergence of resistance to it in both mono- and combination therapy is evident and therefore additional drugs are needed to target the cytochrome bc1 complex which are active against atovaquone-resistant parasites. Our study of a number of halogenated alkyl and alkoxy 4(1H)-quinolones highlights the potential for development of “endochin-like quinolones” (ELQ) bearing an extended trifluoroalkyl moiety at the 3-position that exhibit selective antiplasmodial effects in the low nanomolar range and inhibitory activity against chloroquine and atovaquone resistant parasites. Further studies of halogenated alkyl and alkoxy quinolones may lead to the development of safe and effective therapeutics for use in treatment or prevention of malaria and other parasitic diseases.
Winter, Rolf W.; Kelly, Jane X.; Smilkstein, Martin J.; Dodean, Rozalia; Hinrichs, David; Riscoe, Michael K.
ACH-702 is a new isothiazoloquinolone with potent in vitro and in vivo activities against important bacterial pathogens, including Staphylococcus aureus. In this study, ACH-702 was found to have promising in vitro antibacterial activity against Mycobacterium tuberculosis, with MICs of
Pucci, Michael J; Ackerman, Maria; Thanassi, Jane A; Shoen, Carolyn M; Cynamon, Michael H
ACH-702 is a new isothiazoloquinolone with potent in vitro and in vivo activities against important bacterial pathogens, including Staphylococcus aureus. In this study, ACH-702 was found to have promising in vitro antibacterial activity against Mycobacterium tuberculosis, with MICs of ?1 ?g/ml, comparable to that of the fluoroquinolone moxifloxacin for quinolone-susceptible isolates but superior to that for quinolone-resistant isolates. Biochemical assays involving M. tuberculosis gyrase enzymes indicated that ACH-702 had significantly improved inhibitory activity compared with fluoroquinolones.
Pucci, Michael J.; Ackerman, Maria; Thanassi, Jane A.; Shoen, Carolyn M.; Cynamon, Michael H.
Novel Mannich bases of 7-piperazinylquinolones with kojic acid and chlorokojic acid were designed as new quinolone antibacterials. All compounds showed significant in vitro antibacterial activity against both Gram-positive and Gram-negative bacteria. Particularly, chlorokojic derivative 2b was the most potent compound against Staphylococcus aureus and Pseudomonas aeruginosa (MIC values ?0.19 ?g/mL). Its activity was 4-8 times more than that of standard drug norfloxacin. The molecular docking study of compound 2b further supported the molecular basis of the designed compounds. PMID:23974018
Emami, Saeed; Ghafouri, Ebrahim; Faramarzi, Mohammad Ali; Samadi, Nasrin; Irannejad, Hamid; Foroumadi, Alireza
The effectiveness of antibacterial agents against 70 strains of clinically isolated multiple-drug resistant Pseudomonas aeruginosa (MDRP) was measured by the micro dilution method. Fifty of all strains (71%) produced metallo-beta-lactamase and the IMP-1 gene was detected by polymerase chain reaction (PCR). The MIC90 (the minimum inhibitory concentration of an antibiotic necessary to inhibit the growth of 90% of bacterial strains) values of biapenem (BIPM), meropenem (MEPM), tazobactam/piperacillin (TAZ/PIPC), sulbactam/ cefoperazone (SBT/CPZ), cefepime (CFPM), ciprofloxacin (CPFX), pazufloxacin (PZFX), amikacin (AMK) and aztreonam (AZT) were found to be 265, 512, 256, 512, 512, 64, 128, 128 and 128 microg/mL, respectively. The in vitro combination effects of antibacterial agents were examined against 62 strains of MDRP and the synergy or additive effects were evaluated by fractional inhibitory concentration (FIC) index calculated by the checkerboard method. The combination of AMK and AZT showed synergy effects on 15/59 (25.4%) strains of MDRP. The synergy and additive effects on the MDRP strains were also found by the other antibacterial agents combination such as TAZ/PIPC and AMK, CFPM and AMK, and SBT/CPZ and AZT. These results suggested the necessity of further investigation of clinical usefulness. PMID:16673578
Maesaki, Shigefumi; Yamaguchi, Toshiyuki; Sasaki, Kazumasa; Hashikita, Giichi; Shibuya, Shunsuke; Watanabe, Masaharu; Takayama, Sadao; Kawakami, Sayoko; Nagasawa, Mitsuaki; Suzuki, Noriyasu; Uchida, Takashi; Okabe, Tadashi; Kobayashi, Sugako
The present study was designed to investigate the in vivo drug release and antibacterial properties of a novel mesoporous hydroxyapatite/chitosan (mesoHA-CS) composite loaded with vancomycin (VCM). VCM-mesoHA/CS composite was prepared via a freeze-drying method. The successful loading of VCM in the composite scaffold was verified by FT IR analyses. SEM observation revealed the mesoporous structure of the VCM-mesoHA/CS composite with the pore size of 50-100 µm. Medicated composites were then implanted into the muscular pockets of extremity in rabbits. The results demonstrated that local VCM concentration in muscle tissue could maintain higher than the minimum inhibitory concentration at the site of implantation for long time (i.e. 4 weeks). As a result, the number of viable methicillin-resistant Staphylococcus aureus (MRSA) on mesoHA/CS could be significantly suppressed after the VCM-mesoHA/CS implantation. These results indicated that the mesoHA/CS composite may be promising scaffold as drug storage and release vehicle applied for local antibacterial drug release and bone repair. PMID:22823893
Zhang, Jingzhe; Wang, Chenyu; Wang, Jincheng; Qu, Yang; Liu, Guangyao
A series of new dicarboxylic acid derivatives of 1,3,4-thiadiazines, 1,4-benzopiperizines, 1,4-thiazines, 1,3-thiazoles, 1,3-oxazoles and 1,3-imidazoles have been synthesized in 80-87% yield by the environmentally benign microwave induced technique involving the cyclocondensation of 2,3-dibromosuccinic acid with 2-aminothiophenol, o-phenylene diamine, 1,2,4-triazole, amidinothiocarbamide, amidinocarbamide and guanidine hydrochloride. The structures of all newly synthesized compounds have been established on the basis of analytical and spectral data. Evaluation of antibacterial and antifungal activity showed that almost all compounds exhibited better results than reference drugs thus they could be promising candidates for novel drugs.
Dabholkar, V. V.; Parab, S. D.
The objective of the present study was to prepare clarithromycin (CLR) loaded biodegradable nanoparticles (NPS), with a view to investigate its physicochemical properties and anti-bacterial activity. PLGA was used as a biodegradable polymer and the particles were prepared by nano-precipitation method in 3 different drugs to polymer ratios. Evaluation of the physicochemical properties of the prepared nanoparticles was performed using encapsulation efficiency, nanoparticle production yield, dissolution studies, particle size analysis, zeta potential determination, differential scanning calorimetry, Fourier-transform infrared spectroscopy and X-ray powder diffractometry. The antimicrobial activity against Staphylococcus aureus was determined using serial dilution technique to achieve the minimum inhibitory concentration (MIC) of NPs. The particles were between 189 and 280 nm in size with narrow size distribution, spherical shape and 57.4-80.2% entrapment efficiency. Zeta potential of the NPs was fairly negative. The DSC thermograms and X-ray diffraction patterns revealed reduced drug crystallinity in the NPs. FT-IR spectroscopy demonstrated possible noncovalent interactions between the drug and polymer. In vitro release study showed an initial burst followed by a plateau during a period of 24h. The NPs were more effective than intact CLR against S. aureus so that the former showed equal antibacterial effect at 1/8 concentration of the intact drug. In conclusion, the prepared CLR nanoparticles are more potent against S. aureus with improved MICs and appropriate physicochemical properties that may be useful for other susceptible microorganisms and could be an appropriate candidate for intravenous, ocular and oral and topical preparations. PMID:21752610
Mohammadi, Ghobad; Nokhodchi, Ali; Barzegar-Jalali, Mohammad; Lotfipour, Farzaneh; Adibkia, Khosro; Ehyaei, Nasrin; Valizadeh, Hadi
\\u000a The first of the antiinfective agents belonging to the quinolone class was discovered 50 years ago. Since that time many thousands\\u000a of analogs have been prepared and nearly two dozen examples have found clinical use. New agents are still being introduced\\u000a at a significant pace and research continues to be intensive in this area. With the passage of time and
Lester A. Mitscher; Zhenkun Ma
Background: The risk of hemorrhage when coumarin anticoagulants are used sharply increases when the international normalized ratio (INR) is ?6.0. Such overanticoagulation may be caused by drug interactions. We performed a case-control study among previously stable outpatients of an anticoagulation clinic using phenprocoumon or acenocoumarol to identify changes in the use of potentially interacting drugs related to overanticoagulation.Methods: Three hundred
Fernie J. A. Penning-van Beest; Erik van Meegen; Frits R. Rosendaal; Bruno H. Stricker
The effects of new quinolones on the immune system have been mainly studied in vitro. Despite some conflicting results due to variations in study methodologies, certain conclusions can be drawn. Clinically relevant concentrations of most quinolones seem to have no direct effect on isolated immune parameters such as phagocytic cell functions, lymphocyte proliferation, immunoglobulin production, gamma-interferon secretion and bone-marrow progenitor
As a means of gaining information on the selectivity of quinolone antibacterial agents, we examined their effect on four topoisomerases, topoisomerases I and II purified from Escherichia coli and calf thymus. The inhibition of supercoiling and relaxation activities was monitored by using the classical gel electrophoresis assay. Eight quinolones were assayed by using the four enzymes. Gyrase was much more sensitive to quinolones than the other topoisomerases which can therefore be inhibited by moderate concentrations of certain quinolones. No good correlation was observed between the activity on gyrase and on the other enzymes, since the ratio varied from 15 to more than 8,500. On the contrary, there was a good correlation between early inhibition of DNA synthesis, inhibition of gyrase, and MICs. Images
Moreau, N J; Robaux, H; Baron, L; Tabary, X
We report that point mutations causing alteration of the fourth alpha-helix (?4-helix) of the CAP homology domain of eukaryotic (Saccharomyces cerevisiae) type II topoisomerases (Ser740Trp, Gln743Pro, and Thr744Pro) change the selection of type II topoisomerase-mediated DNA cleavage sites promoted by Ca2+ or produced by etoposide, the fluoroquinolone CP-115,953, or mitoxantrone. By contrast, Thr744Ala substitution had minimal effect on Ca2+- and drug-stimulated DNA cleavage sites, indicating the selectivity of single amino acid substitutions within the ?4-helix on type II topoisomerase-mediated DNA cleavage. The equivalent mutation in the gene for Escherichia coli gyrase causing Ser83Trp also changed the DNA cleavage pattern generated by Ca2+ or quinolones. Finally, Thr744Pro substitution in the yeast type II topoisomerase rendered the enzyme sensitive to antibacterial quinolones. This study shows that the ?4-helix within the conserved CAP homology domain of type II topoisomerases is critical for selecting the sites of DNA cleavage. It also demonstrates that selective amino acid residues in the ?4-helix are important in determining the activity and possibly the binding of quinolones to the topoisomerase II-DNA complexes.
Strumberg, Dirk; Nitiss, John L.; Dong, Jiaowang; Walker, Jerrylaine; Nicklaus, Marc C.; Kohn, Kurt W.; Heddle, Jonathan G.; Maxwell, Anthony; Seeber, Siegfried; Pommier, Yves
Quinolones, in addition to their antibacterial activities, act as immunomodulators. Osteopontin (OPN), a member of the extracellular matrix proteins, was found to play a role in the immune and inflammatory response. We found that quinolones significantly enhanced OPN secretion, namely, garenoxacin (220%), moxifloxacin (62%), gatifloxacin (82%), sparfloxacin, (79%), and sitafloxacin (60%). Enhancement of OPN secretion was shown to be due to the effect of quinolones on the OPN gene promoter activity. We also examined the role of quinolones on apoptosis and found that sparfloxacin decreased the late apoptosis of A549 cells, but garenoxacin did not show the antiapoptotic effect. The antiapoptotic effects of quinolones do not appear to be associated with OPN elevation.
Shiratori, Beata; Zhang, Jing; Usami, Osamu; Chagan-Yasutan, Haorile; Suzuki, Yasuhiko; Nakajima, Chie; Uede, Toshimitsu
Quinolones, in addition to their antibacterial activities, act as immunomodulators. Osteopontin (OPN), a member of the extracellular matrix proteins, was found to play a role in the immune and inflammatory response. We found that quinolones significantly enhanced OPN secretion, namely, garenoxacin (220%), moxifloxacin (62%), gatifloxacin (82%), sparfloxacin, (79%), and sitafloxacin (60%). Enhancement of OPN secretion was shown to be due to the effect of quinolones on the OPN gene promoter activity. We also examined the role of quinolones on apoptosis and found that sparfloxacin decreased the late apoptosis of A549 cells, but garenoxacin did not show the antiapoptotic effect. The antiapoptotic effects of quinolones do not appear to be associated with OPN elevation. PMID:22430970
Shiratori, Beata; Zhang, Jing; Usami, Osamu; Chagan-Yasutan, Haorile; Suzuki, Yasuhiko; Nakajima, Chie; Uede, Toshimitsu; Hattori, Toshio
AIM: To provide baseline data on the levels and patterns of antibacterial drug resistance expressed by Gram-negative bacteria isolated from poultry carcasses in New Zealand.METHODS: Between July and December 2006, isolates of Escherichia coli (n=407) and Salmonella spp. (n=3) originating from carcass-rinse samples were submitted by testing laboratories affiliated to five major poultry processing plants. Isolates of Campylobacter jejuni (n=193)
EJ Pleydell; L Rogers; E Kwan
An agar plate method was established to screen synergistic antibacterial agents other than ?-lactamase inhibitors. By using this method, a strain Aspergillus sp136 was selected for further studies. From the metabolites of this strain, a synergistic antibacterial compound was isolated by bioautographic TLC assay-guided fractionation and identified as helvolic acid. The synergistic effect of helvolic acid to penicillin was about
Ling Qin; Bogang Li; Jiafa Guan; Guolin Zhang
Bacterial antigens, such as intestinal microflora, are known to play a role in the pathogenesis of human inflammatory bowel disease (IBD). Tylosin, a macrolide antimicrobial agent, has proven to be effective in cat and dog chronic colitis, but the reasons underlying this efficacy are still unclear. In the present study we evaluated the effects of tylosin on 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in the rat, in comparison with the antibacterial drug metronidazole and the corticosteroid budesonide. Colitis was induced by a single intrarectal administration of 10 mg TNBS under light ether anesthesia. Tylosin (20 mg/kg twice a day), metronidazole (160 mg/kg twice a day) and budesonide (500 microg/kg once a day) were given orally for up to 6 days to separate groups of rats. The animals were sacrificed after 6 days and colonic lesions evaluated (colon weight, macroscopic and histologic damage, myeloperoxidase activity). Tylosin and metronidazole significantly lowered macroscopic lesion score, reduced colon weight, the severity of histologic lesions and myeloperoxidase activity; budesonide did not significantly change the parameters of colonic inflammation. These data indicate a protective effect of tylosin against intestinal inflammation, suggesting a major role for bacteria, anaerobes in particular, in the development of TNBS-induced mucosal damage. PMID:15756055
Menozzi, Alessandro; Pozzoli, Cristina; Poli, Enzo; Lazzaretti, Mirca; Cantoni, Anna; Grandi, Daniela; Giovannini, Elena; Coruzzi, Gabriella
A novel series of quinolone triazoles were synthesized and characterized by IR, NMR, MS and HRMS spectra. All the newly prepared compounds were screened for their antimicrobial activities against seven bacteria and four fungi. Bioactive assay manifested that most of new compounds exhibited good or even stronger antibacterial and antifungal activities against the tested strains including multi-drug resistant MRSA in comparison with reference drugs Norfloxacin, Chloromycin and Fluconazole. The preliminary interactive investigations of compound 6b with calf thymus DNA by fluorescence and UV-vis spectroscopic methods revealed that compound 6b could effectively intercalate DNA to form compound 6b-DNA complex which might block DNA replication and thus exert its antimicrobial activities. PMID:23602443
Cui, Sheng-Feng; Ren, Yu; Zhang, Shao-Lin; Peng, Xin-Mei; Damu, Guri L V; Geng, Rong-Xia; Zhou, Cheng-He
The in vitro antibacterial activities of nemonoxacin (TG-873870), a novel nonfluorinated quinolone, against 770 clinical isolates were investigated. Nemonoxacin (tested as its malate salt, TG-875649) showed better in vitro activity than ciprofloxacin and levofloxacin against different species of staphylococci, streptococci, and enterococci, Neisseria gonorrhoeae, and Haemophilus influenzae. The in vitro activity of TG-875649 was also comparable to or better than that of moxifloxacin against these pathogens, which included ciprofloxacin-resistant, methicillin-resistant Staphylococcus aureus and levofloxacin-resistant Streptococcus pneumoniae.
Lauderdale, Tsai-Ling; Shiau, Yih-Ru; Lai, Jui-Fen; Chen, Hua-Chien; King, Chi-Hsin R.
Development of new mechanisms of resistance and relatively easy and fast transferring of resistance genes between cells have resulted in emergence of large number of multi-drug resistant bacteria in recent years. Therefore, it is important to intensively search for new, effective compounds possessing antibacterial potential and apply them as active ingredients of medicinal products. This procedure may lead to eradication of clinically relevant, dangerous bacteria. In the twentyfirst century, three new classes of antibacterial agents: oxazolidinones, lipopeptides and pleuromutilins were introduced into the therapy. Compounds from the last group, such as tiamulin, were used previously, but only in veterinary. New 18 antimicrobial compounds, belonging to known therapeutic groups, have been registered since 2000. The largest group among antibacterial chemotherapeutics is quinolones. Group of natural compounds includes: new carbapenems, cephalosporins of V generation and other agents, like telithromycin, tigecycline, telavancin and fidaxomicin. This article is a part of the series associated with searching for new antibacterial agents and it relates to new antibiotics and antibacterial chemotherapeutics approved for the world-wide market since 2000. The next parts of this cycle will be devoted to compounds ongoing the clinical trials. PMID:23484382
Karpiuk, Izabela; Tyski, Stefan
The newer quinolones, the fluoroquinolones, are represented by norfloxacin, ciprofloxacin, ofloxacin, and newer agents such as temafloxacin. These agents represent an improvement over their quinolone counterparts in many ways, including a wider spectrum of antimicrobial activity, improved pharmacokinetic properties, clinical efficacy against a wider range of diseases, and fewer and less severe adverse effects. The focus of preclinical evaluation of fluoroquinolone toxicity is guided by earlier data gathered from the quinolones on the juvenile joint, the kidney, the eye, and the central nervous system (CNS). Animal studies with the fluoroquinolones (norfloxacin, ciprofloxacin, ofloxacin, and temafloxacin) show similar arthropathic damage to the joints of young animals as did the earlier investigations with quinolones. Effects on the kidney that have been reported with quinolones and fluoroquinolones include mild interstitial nephritis, occult blood in urine, decreased renal function, increased renal weight, and crystalluria. These effects are not believed to be a direct toxic effect, but secondary to precipitation of foreign material in the kidney with a neutral or alkaline urine. Because human urine is not normally alkaline, related toxicities should theoretically not be a problem, and clinical data to date generally support this thesis. Ocular toxicity consisting of lenticular opacities in rats and dogs, electrical and histopathologic changes in cats, and electrical changes in dogs have been reported after fluoroquinolone administration; this toxicity does not appear to be a problem in human use. CNS effects have been noted in both animals and humans. Convulsions have been observed with concomitant administration of enoxacin and fenbufen. PMID:1767805
Patterson, D R
Gatifloxacin is an antibacterial agent belonging to the fourth-generation fluoroquinolone family. Four piperazine-linked fluoroquinolone dimers of Gatifloxacin were observed during the laboratory process for Gatifloxacin and they were identified. The present work describes the origin, synthesis, characterization, and control of these dimers along with the synthesis of Despropylene Gatifloxacin (metabolite).
Garaga, Srinivas; Raghava Reddy, Ambati V.; Prabahar, Koilpillai Joseph; Korupolu, Raghu Babu; Sanasi, Paul Douglas
Currently, a standard third-line therapy for Helicobacter pylori (H. pylori) eradication remains to be established. Quinolones show good oral absorption, no major side effects, and marked activity against H. pylori. Several authors have studied quinolone-based third-line therapy and reported encouraging results, with the reported H. pylori cure rates ranging from 60% to 84%. Resistance to quinolones is easily acquired, and the resistance rate is relatively high in countries with a high consumption rate of these drugs. We recently reported a significant difference in the eradication rate obtained between patients infected with gatifloxacin-susceptible and gatifloxacin-resistant H. pylori, suggesting that the selection of quinolones for third-line therapy should be based on the results of drug susceptibility testing. As other alternatives of third-line rescue therapies, rifabutin-based triple therapy, high-dose proton pump inhibitor/amoxicillin therapy and furazolidone-based therapy have been suggested.
Nishizawa, Toshihiro; Suzuki, Hidekazu; Hibi, Toshifumi
Antibacterials play a key role in the treatment of bone infections and appropriate surgical prophylaxis. The rate and extent of penetration of antimicrobials into bone has been assessed and shown to be important for successful treatment in numerous studies. However, no recent review or critical evaluation of the analytical techniques is available. This review compares established and new sample preparation and analytical methods to measure bone concentrations. We performed a systematic literature search in MEDLINE, EMBASE, conference abstracts and references from published articles on bone penetration of antibacterials. This article focuses on the standardization of drug analysis in bone, the extent and rate of bone penetration of antibacterials, and the design, evaluation and reporting techniques of pharmacokinetic studies of bone penetration. The focus is on studies conducted between 1998 and 2007, since a previous review was published in 1999. WinNonlin Professional version 5.0.1 software was used for statistics. Very different methods for sample preparation, drug analysis, data handling and reporting have been employed in bone penetration studies. There is substantial variability in the reported mean bone penetration between drugs and between different studies of the same drug. Quinolones, macrolides and linezolid have mean bone : serum concentration ratios that are commonly between 0.3 and 1.2, and higher ratios have been found for azithromycin (bone concentration in mg/kg of total bone). The ratios are usually between 0.15 and 0.3 for cephalosporins and glycopeptides, and between 0.1 and 0.3 for penicillins. Cephalosporins and penicillins have shown significantly lower (p < 0.05) concentration ratios than linezolid. For 20 of 25 different drugs, the ratios were higher for cancellous bone than for cortical bone. The available data show a larger extent of bone penetration for quinolones, macrolides and linezolid than for beta-lactams. The bone penetration of penicillins and cephalosporins was significantly lower than that of linezolid. Guidelines on sample preparation, drug analysis, study design and pharmacokinetic evaluation of bone penetration studies are vitally needed. PMID:19271782
Landersdorfer, Cornelia B; Bulitta, Jürgen B; Kinzig, Martina; Holzgrabe, Ulrike; Sörgel, Fritz
We have cloned the DNA gyrase and topoisomerase IV genes of Enterococcus faecalis to examine the actions of quinolones against E. faecalis genetically and enzymatically. We first generated levofloxacin-resistant mu- tants of E. faecalis by stepwise selection with increasing drug concentrations and analyzed the quinolone resistance-determining regions of gyrA and parC from the resistant mutants. Isogenic mutants with low-level resistance
Yoshikuni Onodera; Jun Okuda; Mayumi Tanaka; Kenichi Sato
Quinolones possess favourable antibacterial and pharmacokinetic characteristics and are often used as anti-infective agents in adults. They are contraindicated in children and adolescents because they damage weight-bearing joints in juvenile animals. In addition, they possess a tendotoxic potential. Since ciprofloxacin has been used off-label for decades in children and adolescents, it is known today that no pronounced risks for arthropathies
Judith Sendzik; Hartmut Lode; Ralf Stahlmann
The bifunctional enzyme methylenetetrahydrofolate dehydrogenase – cyclohydrolase (FolD) is identified as a potential drug target in Gram-negative bacteria, in particular the troublesome Pseudomonas aeruginosa. In order to provide a comprehensive and realistic assessment of the potential of this target for drug discovery we generated a highly efficient recombinant protein production system and purification protocol, characterized the enzyme, carried out screening of two commercial compound libraries by differential scanning fluorimetry, developed a high-throughput enzyme assay and prosecuted a screening campaign against almost 80,000 compounds. The crystal structure of P. aeruginosa FolD was determined at 2.2 Ĺ resolution and provided a template for an assessment of druggability and for modelling of ligand complexes as well as for comparisons with the human enzyme. New FolD inhibitors were identified and characterized but the weak levels of enzyme inhibition suggest that these compounds are not optimal starting points for future development. Furthermore, the close similarity of the bacterial and human enzyme structures suggest that selective inhibition might be difficult to attain. In conclusion, although the preliminary biological data indicates that FolD represents a valuable target for the development of new antibacterial drugs, indeed spurred us to investigate it, our screening results and structural data suggest that this would be a difficult enzyme to target with respect to developing the appropriate lead molecules required to underpin a serious drug discovery effort.
Maluf, Fernando V.; McElroy, Stuart; James, Daniel; Frearson, Julie; Gray, David; Hunter, William N.
Tolerability data from reports to Federal Drug Authorities, information from drug companies, medical literature, and personal experience are cited. Tolerability data regarding norfloxacin were derived from more than 31,000 patients in a phase IV study; ofloxacin from more than 14,000 patients in a phase IV study; and ciprofloxacin from more than 8,000 patients during phase II and phase III studies. Adverse experiences occurred in 6.8% of patients treated with norfloxacin, 9.1% with ciprofloxacin, and 9.3% with ofloxacin. The most frequent adverse effects involved the gastrointestinal tract. Untoward effects were generally mild and reversible when therapy was discontinued. PMID:2191868
Shah, P M; Mulert, R
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.
BACKGROUND: Antibacterial peptides are one of the effecter molecules of innate immune system. Over the last few decades several antibacterial peptides have successfully approved as drug by FDA, which has prompted an interest in these antibacterial peptides. In our recent study we analyzed 999 antibacterial peptides, which were collected from Antibacterial Peptide Database (APD). We have also developed methods to
Sneh Lata; Nitish K. Mishra; Gajendra P. S. Raghava
The fluoroquinolones (FQs) are important agents for the treatment of mycobacterial infections. In leprosy, the use of FQs has enabled a dramatic shortening of formerly long and complicated therapy. Both animal and human studies support the inclusion of certain FQs as a cornerstone of leprosy therapy. In tuberculosis (TB), particularly in multidrug-resistant (MDR) infections, the place of the major antimycobacterial FQs is less clear as there is widespread resistance to these agents in areas of the world in which MDR-TB and extensively drug-resistant (XDR)-TB are prevalent, particularly in Southeast Asia. The place of the newly developed FQ-related diarylquinoline compound known as bedaquiline in the treatment of drug-resistant TB is unclear; however, human studies suggest that it might be effective for this indication. PMID:23643393
Rubinstein, Ethan; Keynan, Yoav
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.
Kashi, Tahereh Sadat Jafarzadeh; Eskandarion, Solmaz; Esfandyari-Manesh, Mehdi; Marashi, Seyyed Mahmoud Amin; Samadi, Nasrin; Fatemi, Seyyed Mostafa; Atyabi, Fatemeh; Eshraghi, Saeed; Dinarvand, Rassoul
...reduce the development of drug-resistant bacteria and maintain the effectiveness of (insert...or strongly suspected to be caused by bacteria. (b) In the âIndications and Usage...reduce the development of drug-resistant bacteria and maintain the effectiveness of...
The antibacterial activities of DK-507k, a novel quinolone, were compared with those of other quinolones: ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, sitafloxacin, and garenoxacin (BMS284756). DK-507k was as active as sitafloxacin and was as active as or up to eightfold more active than gatifloxacin, moxifloxacin, and garenoxacin against Streptococcus pneumoniae, methicillin-susceptible and methicillin-resistant Staphylo- coccus aureus, and coagulase-negative staphylococci. DK-507k was as
Tsuyoshi Otani; Mayumi Tanaka; Emi Ito; Yuichi Kurosaka; Yoichi Murakami; Kiyomi Onodera; Takaaki Akasaka; Kenichi Sato
The nasopharynx is the ecological niche where evolution towards resistance occurs in respiratory tract isolates. Dynamics of different bacterial populations in antibiotic-free multibacterial niches are the baseline that antibiotic treatments can alter by shifting the competitive balance in favor of resistant populations. For this reason, antibiotic resistance is increasingly being considered to be an ecological problem. Traditionally, resistance has implied the need for development of new antibiotics for which basic efficacy and safety data are required prior to licensing. Antibiotic development is mainly focused on demonstrating clinical efficacy and setting susceptibility breakpoints for efficacy prediction. However, additional information on pharmacodynamic data predicting absence of selection of resistance and of resistant subpopulations, and specific surveillance on resistance to core antibiotics (to detect emerging resistances and its link with antibiotic consumption in the community) are valuable data in defining the role of a new antibiotic, not only from the perspective of its therapeutic potential but also from the ecologic perspective (countering resistances to core antibiotics in the community). The documented information on cefditoren gleaned from published studies in recent years is an example of the role for an emerging oral antibacterial facing current antibiotic resistance in community-acquired respiratory tract infections.
Aguilar, Lorenzo; Gimenez, Maria-Jose; Barberan, Jose
...to be caused by susceptible bacteria. When culture and susceptibility...development of drug-resistant bacteria. (d) In the âPrecautions...increase the likelihood that bacteria will develop resistance and will not be treatable...
...to be caused by susceptible bacteria. When culture and susceptibility...development of drug-resistant bacteria. (d) In the âPrecautions...increase the likelihood that bacteria will develop resistance and will not be treatable...
A phytochemical investigation of the stems of Waltheria douradinha resulted in isolation of two 4-quinolone alkaloids, waltherione B and vanessine, along with three known alkaloids, waltherione A, antidesmone and O-methyltembamide. Their structures were elucidated on the basis of their 2D NMR spectroscopic analyses, and from X-ray crystallographic analysis of waltherione A and the O-methyl derivative of waltherione B. Additionally, waltherione B and vanessine, and the O- and N-methyl derivatives of waltherione A and waltherione B, were evaluated for their antimicrobial activities; only vanessine displayed any (weak) antimicrobial activity. PMID:18076957
Gressler, Vanessa; Stüker, Caroline Z; Dias, Gilvan de O C; Dalcol, Ionara I; Burrow, Robert A; Schmidt, Juergen; Wessjohann, Ludger; Morel, Ademir F
In an era of increasing resistance to classical antibacterial agents, the synthetic oxazolidinone series of antibiotics has attracted much interest. Zyvoxtrade mark was the first oxazolidinone to be approved for clinical use against infections caused by multi-drug resistant Gram-positive bacteria. In the course of studies directed toward the discovery of novel antibacterial agents, a new series of synthetic phenyl-isoxazolinone agents that displayed potent activity against Gram-positive bacterial strains was recently discovered at Bristol-Myers Squibb. Extensive investigation of various substitutions on the phenyl ring was then undertaken. We report here, the synthesis and antibacterial activity of a series of biaryl isoxazolinone compounds. PMID:15869878
Quesnelle, Claude A; Gill, Patrice; Roy, Stephan; Dodier, Marco; Marinier, Anne; Martel, Alain; Snyder, Lawrence B; D'Andrea, Stanley V; Bronson, Joanne J; Frosco, Marybeth; Beaulieu, Danielle; Warr, Glen A; Denbleyker, Ken L; Stickle, Terry M; Yang, Hyekyung; Chaniewski, Susan E; Ferraro, Cheryl A; Taylor, Dennis; Russell, John W; Santone, Kenneth S; Clarke, Junius; Drain, Rebecca L; Knipe, Jay O; Mosure, Kathleen; Barrett, John F
Malaria is a protozoal parasitic disease that is widespread in tropical and subtropical regions of Africa, Asia, and the Americas and causes more than 800,000 deaths per year. The continuing emergence of multi-drug-resistant Plasmodium falciparum drives the ongoing need for the development of new and effective antimalarial drugs. Our previous work has explored the preliminary structural optimization of 4(1H)-quinolone ester derivatives, a new series of antimalarials related to the endochins. Herein, we report the lead optimization of 4(1H)-quinolones with a focus on improving both antimalarial potency and bioavailability. These studies led to the development of orally efficacious antimalarials including quinolone analogue 20g, a promising candidate for further optimization.
Zhang, Yiqun; Clark, Julie A; Connelly, Michele C.; Zhu, Fangyi; Min, Jaeki; Guiguemde, W. Armand; Pradhan, Anupam; Iyer, Lalitha; Furimsky, Anna; Gow, Jason; Parman, Toufan; El Mazouni, Farah; Phillips, Margaret A.; Kyle, Dennis E.; Mirsalis, Jon; Guy, R. Kiplin
The relationship between the structures of quinolones and their anti-Mycobacterium avium activities has been previously derived by using the Multiple Computer-Automated Structure Evaluation program. A number of substructural constraints required to overcome the resistance of most of the strains have been identified. Nineteen new quinolones which qualify under these substructural requirements were identified by the program and subsequently tested. The results show that the substructural attributes identified by the program produced a successful a priori prediction of the anti-M. avium activities of the new quinolones. All 19 quinolones were found to be active, and 4 of them are as active or better than ciprofloxacin. With these new quinolones, the updated multiple computer-automated structure evaluation program structure-activity relationship analysis has helped to uncover additional information about the nature of the substituents at the C5 and C7 positions needed for optimal inhibitory activity. A possible explanation of drug resistance based on the observation of suicide inactivation of bacterial cytochrome P-450 by the cyclopropylamine moiety has also been proposed and is discussed in this report. Furthermore, we confirm the view that the amount of the uncharged form present in a neutral pH solution plays a crucial role in the drug's penetration ability.
Klopman, G; Li, J Y; Wang, S; Pearson, A J; Chang, K; Jacobs, M R; Bajaksouzian, S; Ellner, J J
Alternative herbal medicine has been used to treat various infections from centuries. Natural plants contain phytoconstituents having similar chemical properties as of synthetic antibiotics. Typhoid fever is a serious infection and failure of its treatment emerged multi-drug resistant (MDR) bugs of Salmonella typhi. Due to multiple and repeated issues with antibiotics efficacy, it became essential to evaluate biological properties of plants from different geographical origins. Mango leaves have been Reported for various medicinal effects like antioxidant, antimicrobial, antihelminthic, antidiabetic and antiallergic etc. Objective of present study was to investigate anti-typhoid properties of acetone mango leaf extract (AMLE) against antibiotic sensitive and MDR S. typhi isolates. A total of 50 isolates of S. typhi including MDR (n=30) and antibiotic sensitive (n=20) were investigated. Staphylococcus aureus (ATCC 25923) and Salmonella typhimurium (ATCC14028) were used as quality control strains. AMLE was prepared and its antibacterial activity was evaluated by agar well diffusion screening method and minimum inhibitory concentration (MIC), by agar dilution technique. Zone of inhibition (mm) of AMLE against MDR and antibiotic sensitive isolates was 18±1.5mm (Mean±S.D). Zone of S. aureus (ATCC 25923) and S. typhimurium (ATCC14028) was 20±1.5mm (Mean±S.D). MIC of AMLE was Reported in range from 10-50 mg/ml. The present study described the inhibitory effects of mango leaves against S. typhi. PMID:23811447
Hannan, Abdul; Asghar, Samra; Naeem, Tahir; Ikram Ullah, Muhammad; Ahmed, Ijaz; Aneela, Syeda; Hussain, Shabbir
Azithromycin, an important member of the azalide subclass is effective against both Gram-positive and Gram-negative organisms. Certain physicochemical properties of the drug like poor water solubility and relatively low bioavailability of 37% due to incomplete absorption after ingestion, aroused the need for the development of a novel drug delivery system to enhance the solubilization potential and antibacterial activity against Staphylococcus aureus at a very low concentration. Cinnamon oil (Cinnamonum zeylanicum)-based microemulsion system formulated using non-ionic surfactant, Tween 20, and water was characterized. The drug-incorporated system F4 (oil to surfactant ratio of 1:4 (v/v)) showed enhanced solubilization of the drug, droplet diameter of 5-8 nm, and a good thermodynamic stability. The effect of surfactant concentration exhibited a negative correlation with droplet size diameter and turbidity and a positive correlation with stability and viscosity. The system was investigated for its antibacterial activity that demonstrated a significantly higher activity at a minimum concentration (4 ?g/ml) of the novel drug-loaded system in comparison with the conventional formulation (128 ?g/ml). Examination through scanning electron microscopy analysis further confirmed a considerable morphologic variation due to alteration in the membrane permeability of the microemulsion-treated system. The small droplet size of the microemulsion system and the antibacterial property of cinnamon oil, together, accounts clearly for the enhanced efficacy of the new formulated system F4 and not just azithromycin alone. Staining with acridine orange/ethidium bromide dyes as examined through fluorescence microscopy also substantiated with the results of membrane permeability of bacteria. Thus, our study discloses a potential oral drug delivery system of azithromycin with improved biocompatibility. PMID:23800858
Nirmala, M Joyce; Mukherjee, Amitava; Chandrasekaran, N
\\u000a Abstract\\u000a Drug-induced hepatotoxicity is a frequent cause of liverdisease and acute liver failure, particularly in patients treatedwith\\u000a multiple drugs. Several antibacterial drugs have thepotential to cause severe liver injury and failure. This articleaims to\\u000a increase the awareness and understanding of druginducedliver injury (DILI) due to antibacterial drugs. Itreviews the pattern\\u000a of antibacterial DILI and provides detailson molecular mechanisms and toxicogenomics,
J. M. Leitner; W. Graninger; F. Thalhammer
To identify novel antibiotics against Mycobacterium tuberculosis, we performed a hierarchical structure-based drug screening (SBDS) targeting the enoyl-acyl carrier protein reductase (InhA) with a compound library of 154,118 chemicals. We then evaluated whether the candidate hit compounds exhibited inhibitory effects on the growth of two model mycobacterial strains: Mycobacterium smegmatis and Mycobacterium vanbaalenii. Two compounds (KE3 and KE4) showed potent inhibitory effects against both model mycobacterial strains. In addition, we rescreened KE4 analogs, which were identified from a compound library of 461,383 chemicals through fingerprint analysis and genetic algorithm-based docking simulations. All of the KE4 analogs (KES1-KES5) exhibited inhibitory effects on the growth of M. smegmatis and/or M. vanbaalenii. Based on the predicted binding modes, we probed the structure-activity relationships of KE4 and its analogs and found a correlative relationship between the IC50 values and the interaction residues/LogP values. The most potent inhibitor, compound KES4, strongly and stably inhibited the long-term growth of the model bacteria and showed higher inhibitory effects (IC50 = 4.8 ?M) than isoniazid (IC50 = 5.4 ?M), which is a first-line drug for tuberculosis therapy. Moreover, compound KES4 did not exhibit any toxic effects that impede cell growth in several mammalian cell lines and enterobacteria. The structural and experimental information of these novel chemical compounds will likely be useful for the development of new anti-TB drugs. Furthermore, the methodology that was used for the identification of the effective chemical compound is also likely to be effective in the SBDS of other candidate medicinal drugs. PMID:23600706
Kinjo, Tomohiro; Koseki, Yuji; Kobayashi, Maiko; Yamada, Atsumi; Morita, Koji; Yamaguchi, Kento; Tsurusawa, Ryoya; Gulten, Gulcin; Komatsu, Hideyuki; Sakamoto, Hiroshi; Sacchettini, James C; Kitamura, Mitsuru; Aoki, Shunsuke
Bacteria capable of producing exoproteases were isolated from intermediate products of microbial lipase. The proteolytic enzymes produced by the bacteria were able to inactivate 20 to 80 per cent of the lipase depending on the time of incubation, protease production by the contaminating microbe and the experimental conditions. Antibiotics and antiseptics inhibiting growth of bacteria prevented or limited their inactivating action on lipase. Except catamine, the tested antimicrobial drugs as such had no effect on lipase activity. PMID:1304126
Malkova, E M
DFT calculations for the acid-catalyzed hydrolysis of several maleamic acid amide derivatives revealed that the reaction rate-limiting step is determined on the nature of the amine leaving group. Further, it was established that when the amine leaving group was a secondary amine, acyclovir or cefuroxime moiety the tetrahedral intermediate formation was the rate-limiting step such as in the cases of acyclovir ProD 1- ProD 4 and cefuroxime ProD 1- ProD 4. In addition, the linear correlation between the calculated and experimental rates provided a credible basis for designing prodrugs for masking bitter taste of the corresponding parental drugs which have the potential to release the parent drug in a sustained release fashion. For example, based on the DFT calculated rates the predicted t?/? (a time needed for 50 % of the reactant to be hydrolyzed to products) for cefuroxime prodrugs, cefuroxime ProD 1- ProD 4, were 12 min, 18 min, 200 min and 123 min, respectively. PMID:23420399
Rare side effects on the central nervous system including dizziness, restlessness, and even very rare convulsions as reported during the course of antibiotic treatment with quinolones were the topic of a well-controlled in vitro approach. The excitability of brain matter was tested by electrically evoking field potentials in the CA1 region of the rat hippocampus in vitro. Direct effects of nalidixic acid, enoxacin, pefloxacin, norfloxacin, ofloxacin, and ciprofloxacin were found to occur as a dose-dependent increase in amplitude of this field potential, which is in line with the view that the quinolones increase excitability. The highest increase was found with enoxacin and nalidixic acid, and the lowest increase was found with ciprofloxacin. In order to keep the potential risk of the antibiotic therapy as low as possible, ciprofloxacin might be the drug of choice of the quinolones. In contrast to the quinolones, which only increased the amplitudes of electrically evoked potentials, fenbufen induced spontaneous firing in the pyramidal cell layer without stimulation in addition to its dose-dependent effects on the amplitudes of the evoked potentials. Threshold doses of the quinolones tested (0.25 microM) increased the amplitudes of evoked potentials in the presence of an otherwise ineffective concentration of fenbufen (1 microM) to different degrees, ranging from 39.2% for ciprofloxacin to 72.6% for enoxacin.
Dimpfel, W; Spuler, M; Dalhoff, A; Hofmann, W; Schluter, G
Rare side effects on the central nervous system including dizziness, restlessness, and even very rare convulsions as reported during the course of antibiotic treatment with quinolones were the topic of a well-controlled in vitro approach. The excitability of brain matter was tested by electrically evoking field potentials in the CA1 region of the rat hippocampus in vitro. Direct effects of nalidixic acid, enoxacin, pefloxacin, norfloxacin, ofloxacin, and ciprofloxacin were found to occur as a dose-dependent increase in amplitude of this field potential, which is in line with the view that the quinolones increase excitability. The highest increase was found with enoxacin and nalidixic acid, and the lowest increase was found with ciprofloxacin. In order to keep the potential risk of the antibiotic therapy as low as possible, ciprofloxacin might be the drug of choice of the quinolones. In contrast to the quinolones, which only increased the amplitudes of electrically evoked potentials, fenbufen induced spontaneous firing in the pyramidal cell layer without stimulation in addition to its dose-dependent effects on the amplitudes of the evoked potentials. Threshold doses of the quinolones tested (0.25 microM) increased the amplitudes of evoked potentials in the presence of an otherwise ineffective concentration of fenbufen (1 microM) to different degrees, ranging from 39.2% for ciprofloxacin to 72.6% for enoxacin. PMID:1929256
Dimpfel, W; Spüler, M; Dalhoff, A; Hofmann, W; Schlüter, G
The results of identification of 710 clinical strains of anaerobic microorganisms isolated from the pathological foci of patients with maxillofacial diseases are presented. The species composition of the microflora associations in the cases with abscesses, phlegmon, lymphadenitis, osteomyelitis and parodontitis is described. Along with a high frequency of nonsporulating anaerobes, staphylococci, microaerophilic streptococci and in the cases with parodontitis actinomycetes, Bacillus licheniformis and Bacillus coagulans strains (1.6-15% of the isolated strains) were first detected in cases with various forms of the disease. Two groups of the drugs effective against the anaerobes were identified by the data on the antibiotic sensitivity. The lowest MICs along with the activity broad spectrum were defined for gramicidin, levomycetin and nitazol. PMID:1300935
Oleinik, I I; Ponomareva, A G; Tsarev, V N; Kurakin, A V; Ushakov, R V; Kalinin, A I; Ushakova, T V
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.
Suzuki, Satoru; Hoa, Phan Thi Phuong
The emergence of resistance against most current drugs emphasizes the need to develop new approaches to control bacterial pathogens, particularly Staphylococcus aureus. Bacterial fatty acid synthesis is one such target that is being actively pursued by several research groups to develop anti-Staphylococcal agents. Recently, the wisdom of this approach has been challenged based on the ability of a Gram-positive bacterium to incorporate extracellular fatty acids and thus circumvent the inhibition of de novo fatty acid synthesis. The generality of this conclusion has been challenged, and there is enough diversity in the enzymes and regulation of fatty acid synthesis in bacteria to conclude that there isn’t a single organism that can be considered typical and representative of bacteria as a whole. We are left without a clear resolution to this ongoing debate and await new basic research to define the pathways for fatty acid uptake and that determine the biochemical and genetic mechanisms for the regulation of fatty acid synthesis in Gram-positive bacteria. These crucial experiments will determine whether diversity in the control of this important pathway accounts for the apparently different responses of Gram-positive bacteria to the inhibition of de novo fatty acid synthesis in presence of extracellular fatty acid supplements.
Parsons, Joshua B.; Rock, Charles O.
l-Arginine deiminase (ADI) catalyzes the irreversible hydrolysis of arginine to citrulline and ammonia. ADI is involved in the first step of the most widespread anaerobic route of arginine degradation. ADI, missing in high eukaryotes, is a potential antimicrobial and antiparasitic drug target. We have determined the crystal structure of ADI from Pseudomonas aeruginosa by the multi-wavelength anomalous diffraction method at 2.45 A resolution. The structure exhibits similarity to other arginine-modifying or substituted arginine-modifying enzymes such as dimethylarginine dimethylaminohydrolase (DDAH), arginine:glycine amidinotransferase, and arginine:inosamine-phosphate amidinotransferase, despite the lack of significant amino acid sequence homology to these enzymes. The similarity spans a core domain comprising five betabetaalphabeta motifs arranged in a circle around a 5-fold pseudosymmetry axis. ADI contains an additional alpha-helical domain of novel topology inserted between the first and the second betabetaalphabeta modules. A catalytic triad, Cys-His-Glu/Asp (arranged in a different manner from that of the thiol proteases), seen in the other arginine-modifying enzymes is also conserved in ADI, as well as many other residues involved in substrate binding. Based on this conservation pattern and the assumption that the substrate binding mode is similar to that of DDAH, an ADI catalytic mechanism is proposed. The main players are Cys-406, which mounts the nucleophilic attack on the carbon atom of the guanidinium group of arginine, and His-278, which serves as a general base. PMID:14701825
Galkin, Andrey; Kulakova, Liudmila; Sarikaya, Elif; Lim, Kap; Howard, Andrew; Herzberg, Osnat
This study compared the utilization and cost of antibacterial agents in surgical units of 2 government hospitals in Palestine. The consumption and cost of drugs was estimated in the units over a 1-month period in 2010 using the anatomical therapeutic chemical classification and defined daily doses (DDD) per 100 bed-days. The total consumption of antibacterial agents was 414.1 DDD and 591.5 DDD at Thabet and Rafidia hospitals respectively. These corresponded to 133.6 DDD/100 bed-days and 162.2 DDD/100 bed-days respectively, figures that were higher than those reported in surgical units in many other countries. Total cost of antibacterial agents during the study period was 24 800 and 23481 NIS for Rafidia and Thabet hospitals respectively. Approximately 11.2% and 18.0% of the total antibiotic DDD in Rafidia and Thabet hospitals were given to patients with clean surgeries in which antibiotic prophylaxis is not indicated. PMID:22888623
Sweileh, W M; Adas, S O; Sawalha, A F; Taha, A S Abu
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
Nakamura, Tatsuya; Komatsu, Masaru
Two desferrioxamine B-ciprofloxacin conjugates with “trimethyl-lock” based linkers that are designed to release the antibiotic after esterase or phosphatase-mediated hydrolysis were synthesized. The potential esterase-sensitive conjugate 13 displayed moderate to good antibacterial activities against selected ferrioxamine-utilizing bacteria, although the activities were lower than the parent drug ciprofloxacin. However, the potential phophatase-sensitive conjugate 23 was inactive against the same panel of organisms tested. These properties appeared to be related to the activating efficiency of the linker by the enzyme and to the outer membrane protein recognition of the chemically modified siderophore used in the conjugate.
Agar dilution MIC determination was used to compare the activity of DK-507k with those of ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, sitafloxacin, amoxicillin, cefuroxime, erythromycin, azithromycin, and clarithromycin against 113 penicillin-susceptible, 81 penicillin-intermediate, and 67 penicillin-resistant pneumococci (all quinolone susceptible). DK-507k and sitafloxacin had the lowest MICs of all quinolones against quinolone-susceptible strains (MIC at which 50% of isolates were inhibited [MIC50] and MIC90 of both, 0.06 and 0.125 ?g/ml, respectively), followed by moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. MICs of ?-lactams and macrolides rose with those of penicillin G. Against 26 quinolone-resistant pneumococci with known resistance mechanisms, DK-507k and sitafloxacin were also the most active quinolones (MICs, 0.125 to 1.0 ?g/ml), followed by moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. Mutations in quinolone resistance-determining regions of quinolone-resistant strains were in the usual regions of the parC and gyrA genes. Time-kill testing showed that both DK-507k and sitafloxacin were bactericidal against all 12 quinolone-susceptible and -resistant strains tested at twice the MIC at 24 h. Serial broth passages in subinhibitory concentrations of 10 strains for a minimum of 14 days showed that development of resistant mutants (fourfold or greater increase in the original MIC) occurred most rapidly for ciprofloxacin, followed by moxifloxacin, DK-507k, gatifloxacin, sitafloxacin, and levofloxacin. All parent strains demonstrated a fourfold or greater increase in initial MIC in <50 days. MICs of DK-507k against resistant mutants were lowest, followed by those of sitafloxacin, moxifloxacin, gatifloxacin, ciprofloxacin, and levofloxacin. Four strains were subcultured in subinhibitory concentrations of each drug for 50 days: MICs of DK-507k against resistant mutants were lowest, followed by those of sitafloxacin, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. Exposure to DK-507k and sitafloxacin resulted in mutations, mostly in gyrA.
Browne, Frederick A.; Bozdogan, Bulent; Clark, Catherine; Kelly, Linda M.; Ednie, Lois; Kosowska, Klaudia; Dewasse, Bonifacio; Jacobs, Michael R.; Appelbaum, Peter C.
As part of Meropenem Yearly Susceptibility Test Information Collection\\/USA Surveillance Programme, we monitored the occurrence of quinolone resistance in Escherichia coli over a 10-year period. A total of 271 E. coli isolates from our institution were tested over a 10-year period. Screening for quinolone resistance (qnr) gene was performed. A decline in susceptibility of E. coli isolates to quinolones and
Coralia N. Mihu; Paul R. Rhomberg; Ronald N. Jones; Elizabeth Coyle; Randall A. Prince; Kenneth V. Rolston
We have cloned the DNA gyrase and topoisomerase IV genes of Enterococcus faecalis to examine the actions of quinolones against E. faecalis genetically and enzymatically. We first generated levofloxacin-resistant mutants of E. faecalis by stepwise selection with increasing drug concentrations and analyzed the quinolone resistance-determining regions of gyrA and parC from the resistant mutants. Isogenic mutants with low-level resistance contained a mutation in gyrA, whereas those with higher levels of resistance had mutations in both gyrA and parC. These results suggested that gyrA is the primary target for levofloxacin in E. faecalis. We then purified the recombinant DNA gyrase and topoisomerase IV enzymes of E. faecalis and measured the in vitro inhibitory activities of quinolones against these enzymes. The 50% inhibitory concentrations (IC50s) of levofloxacin, ciprofloxacin, sparfloxacin, tosufloxacin, and gatifloxacin for DNA gyrase were found to be higher than those for topoisomerase IV. In conflict with the genetic data, these results indicated that topoisomerase IV would be the primary target for quinolones in E. faecalis. Among the quinolones tested, the IC50 of sitafloxacin (DU-6859a), which shows the greatest potency against enterococci, for DNA gyrase was almost equal to that for topoisomerase IV; its IC50s were the lowest among those of all the quinolones tested. These results indicated that other factors can modulate the effect of target affinity to determine the bacterial killing pathway, but the highest inhibitory actions against both enzymes correlated with good antienterococcal activities.
Onodera, Yoshikuni; Okuda, Jun; Tanaka, Mayumi; Sato, Kenichi
We conducted a quantitative structure-activity relationship study using a database of 158 quinolones previously tested against Mycobacterium avium-M. intracellulare complex in order to develop a model capable of predicting the activity of new quinolones against the M. avium-M. intracellulare complex in vitro. Topological indices were used as structural descriptors and were related to anti-M. avium-M. intracellulare complex activity by using the linear discriminant analysis (LDA) statistical technique. The discriminant equation thus obtained correctly classified 137 of the 158 quinolones, including 37 of a test group of 44 randomly chosen compounds. This model was then applied to 24 quinolones, including recently developed fluoroquinolones, whose MICs were subsequently determined in vitro by using the Alamar blue microplate assay; the biological results confirmed the model's predictions. The MICs of these 24 quinolones were then treated by multilinear regression (MLR) to establish a model capable of classifying them according to their in vitro activities. Using this model, a good correlation between measured and predicted MICs was found (r2 = 0.88; r2cv [cross-validation correlation] = 0.82). Moxifloxacin, sparfloxacin, and gatifloxacin were the most potent against the M. avium- M. intracellulare complex, with MICs of 0.2, 0.4, and 0.9 ?g/ml, respectively. Finally, virtual modifications of these three drugs were evaluated in LDA and MLR models in order to determine the importance of different substituents in their activity. We conclude that the combination of molecular-topology methods, LDA, and MLR provides an excellent tool for the design of new quinolone structures with enhanced activity.
Gozalbes, Rafael; Brun-Pascaud, Monique; Garcia-Domenech, Ramon; Galvez, Jorge; Girard, Pierre-Marie; Doucet, Jean-Pierre; Derouin, Francis
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 ?g mL-1. Complexes also exhibit SOD-like activity with their IC50 values ranging from 0.717 to 1.848 ?M.
Patel, Mohan N.; Joshi, Hardik N.; Patel, Chintan R.
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 ?g mL(-1). Complexes also exhibit SOD-like activity with their IC(50) values ranging from 0.717 to 1.848 ?M. PMID:23266675
Patel, Mohan N; Joshi, Hardik N; Patel, Chintan R
Pseudomonas aeruginosa which is widely found in the environment, may lead to serious nosocomial infections. Due to its intrinsic resistance to many antibacterial agents, treatment of P.aeruginosa infections usually present difficulty. Quinolones, especially ciprofloxacin, are crutial antibiotics for the treatment of P.aeruginosa infections. However resistance developing to quinolones may become an important problem. Resistance to quinolones is often a result of chromosomal mutations and by the effect of efflux pumps. Recently plasmid-mediated quinolone resistance have been reportedin the members of Enterobacteriaceae family. The gene responsible for this resistance is called qnr. In addition to qnr genes there is also another gene called aac(6?)-Ib-cr responsible for plasmid-mediated quinolone resistance and aminoglycoside resistance. Limited studies which to screen P.aeruginosa strains for the presence of qnr gene region, revealed no positivity. The aim of this study was to investigate the plasmid-mediated quinolone resistance in P.aeruginosa strains isolated from cystic fibrosis patients. A total of 110 P.aeruginosa strains isolated from respiratory tract specimens from the patients were included in the study. Ciprofloxacin susceptibilities of the isolates were detected by Kirby-Bauer disk diffusion method according to CLSI guidelines. The presence of qnrA, qnrB, qnrC, qnrS and aac(6')-Ib-cr genes were searched by multiplex polymerase chain reaction (PCR) with the use of specific individual primer pairs. As positive control strains, Escherichia coli J53 pMG252 (qnrA1 positive), E.coli J53 pMG252 (qnrS1 positive), E.coli J53 pMG258 (qnrB1 and aac(6')-Ib-cr positive), Klebsiella pneumoniae ref.15 (qnrB positive), Enterobacter cloacae ref.287 (qnrS positive), E.coli ref.20 (qnrA positive) and E.coli DH10 conjugated with pHS11 plasmid (qnrC positive) were used. Of 110 P.aeruginosa clinical isolates, 13 were found resistant to ciprofloxacin, while 7 were intermediate. However multiplex PCR yielded no positivity in terms of qnrA, qnrB, qnrC, qnrS and aac(6')-Ib-cr gene regions. In conclusion, although our results indicated that none of the tested P.aeruginosa strains harboured those genes, further multicenter studies with large numbers of isolates are needed to confirm these results. PMID:22090290
Coban, Ahmet Y?lmaz; Tanr?verdi Çayc?, Yeliz; Y?ld?r?m, Tuba; Erturan, Zayre; Durup?nar, Belma; Bozdo?an, Bülent
Mycobacterium leprae, the causative agent of leprosy, is noncultivable in vitro; therefore, evaluation of antibiotic activity against M. leprae relies mainly upon the mouse footpad system, which requires at least 12 months before the results become available. We have developed an in vitro assay for studying the activities of quinolones against the DNA gyrase of M. leprae. We overexpressed in Escherichia coli the M. leprae GyrA and GyrB subunits separately as His-tagged proteins by using a pET plasmid carrying the gyrA and gyrB genes. The soluble 97.5-kDa GyrA and 74.5-kDa GyrB subunits were purified by nickel chelate chromatography and were reconstituted as an enzyme with DNA supercoiling activity. Based on the drug concentrations that inhibited DNA supercoiling by 50% or that induced DNA cleavage by 25%, the 13 quinolones tested clustered into three groups. Analysis of the quinolone structure-activity relationship demonstrates that the most active quinolones against M. leprae DNA gyrase share the following structural features: a substituted carbon at position 8, a cyclopropyl substituent at N-1, a fluorine at C-6, and a substituent ring at C-7. We conclude that the assays based on DNA supercoiling inhibition and drug-induced DNA cleavage on purified M. leprae DNA gyrase are rapid, efficient, and safe methods for the screening of quinolone derivatives with potential in vivo activities against M. leprae.
Matrat, Stephanie; Petrella, Stephanie; Cambau, Emmanuelle; Sougakoff, Wladimir; Jarlier, Vincent; Aubry, Alexandra
Ciprofloxacin was introduced for treatment of patients with cholera in Bangladesh because of resistance to other agents, but its utility has been compromised by the decreasing ciprofloxacin susceptibility of Vibrio cholerae over time. We correlated levels of susceptibility and temporal patterns with the occurrence of mutation in gyrA, which encodes a subunit of DNA gyrase, followed by mutation in parC, which encodes a subunit of DNA topoisomerase IV. We found that ciprofloxacin activity was more recently further compromised in strains containing qnrVC3, which encodes a pentapeptide repeat protein of the Qnr subfamily, members of which protect topoisomerases from quinolone action. We show that qnrVC3 confers transferable low-level quinolone resistance and is present within a member of the SXT integrating conjugative element family found commonly on the chromosomes of multidrug-resistant strains of V. cholerae and on the chromosomes of Escherichia coli transconjugants constructed in the laboratory. Thus, progressive increases in quinolone resistance in V. cholerae are linked to cumulative mutations in quinolone targets and most recently to a qnr gene on a mobile multidrug resistance element, resulting in further challenges for the antimicrobial therapy of cholera.
Kim, Hong Bin; Wang, Minghua; Ahmed, Sabeena; Park, Chi Hye; LaRocque, Regina C.; Faruque, Abu S. G.; Salam, Mohammed A.; Khan, Wasif A.; Qadri, Firdausi; Calderwood, Stephen B.; Jacoby, George A.; Hooper, David C.
Quinolone resistance encoded by the qnr gene and mediated by plasmid pMG252 was discovered in a clinical strain of Klebsiella pneumoniae that was isolated in 1994 at the University of Alabama at Birmingham Medical Center. The gene codes for a protein that protects DNA gyrase from quinolone inhibition and that belongs to the pentapeptide repeat family of proteins. The prevalence of the gene has been investigated by using PCR with qnr-specific primers with a sample of more than 350 gram-negative strains that originated in 18 countries and 24 states in the United States and that included many strains with plasmid-mediated AmpC or extended spectrum ?-lactamase enzymes. qnr was found in isolates from the University of Alabama at Birmingham only during 6 months in 1994, despite the persistence of the gene for FOX-5 ?-lactamase, which is linked to qnr on pMG252. Isolates from other locations were negative for qnr. The prevalence of mcbG in the same sample was also examined. mcbG encodes another member of the pentapeptide repeat family and is involved in immunity to microcin B17, which, like quinolones, targets DNA gyrase. A single clinical isolate contained mcbG on a transmissible R plasmid. This plasmid and one carrying the complete microcin B17 operon slightly decreased sparfloxacin susceptibility but had a much less protective effect than pMG252. Plasmid-mediated quinolone resistance was thus rare in the sample examined.
Jacoby, George A.; Chow, Nancy; Waites, Ken B.
The apicoplast, a plastid-like organelle of Toxoplasma gondii, is thought to be a unique drug target for quinolones. In this study, we assessed the in vitro activity of quinolones against T. gondii and developed new quantitative structure-activity relationship models able to predict this activity. The anti-Toxoplasma activities of 24 quinolones were examined by means of linear discriminant analysis (LDA) using topological indices as structural descriptors. In parallel, in vitro 50% inhibitory concentrations (IC50s) were determined in tissue culture. A multilinear regression (MLR) analysis was then performed to establish a model capable of classifying quinolones by in vitro activity. LDA and MLR analysis were applied to virtual structures to identify the influence of each atom or substituent of the quinolone ring on anti-Toxoplasma activity. LDA predicted that 20 of the 24 quinolones would be active against T. gondii. This was confirmed in vitro for most of the quinolones. Trovafloxacin, grepafloxacin, gatifloxacin, and moxifloxacin were the quinolones most potent against T. gondii, with IC50s of 0.4, 2.4, 4.1, and 5.1 mg/liter, respectively. Using MLR analysis, a good correlation was found between measured and predicted IC50s (r2 = 0.87, cross-validation r2 = 0.74). MLR analysis showed that the carboxylic group at position C-3 of the quinolone ring was not essential for anti-Toxoplasma activity. In contrast, activity was totally dependent on the presence of a fluorine at position C-6 and was enhanced by the presence of a methyl group at C-5 or an azabicyclohexane at C-7. A nucleophilic substituent at C-8 was essential for the activity of gatifloxacin and moxifloxacin.
Gozalbes, Rafael; Brun-Pascaud, Monique; Garcia-Domenech, Ramon; Galvez, Jorge; Girard, Pierre-Marie; Doucet, Jean-Pierre; Derouin, Francis
Anti-VRE and anti-MRSA activities of new quinolone derivatives [The two quinolone derivatives are 8- [3-[(ethylamino) methyl]-1-pyrrodinyl] -7-fluoro-9, 1-[(N-methylimino)methano]-5-oxo-5H-thiazolo[3,2-a]quinolone-4-carboxylic acid (compound A) and 7-fluoro-8-morpholino-9,1-[(N-methylimino) methanol-5-oxo-5H-thiazolo [3,2-a] quinolone-4-carboxylic acid (compound B)] and their synergism with commercial antibiotics were investigated. Compound A exhibited potent antibacterial activity against VRE and MRSA among the five new quinolone compounds tested, and showed superior activity to pefloxacin, ofloxacin and levofloxacin, which are clinically in use these days. With respect to the anti-VRE activity, compound A showed synergism with fosfomycin (FOM), and partial synergism with ampicillin (ABPC), gentaicin (GM), minocycline (MINO) and vancomycin hydrochloride (VCM). Partial synergism in anti-VRE activity was also observed between compound B and GM, MINO, FOM and VCM. Compound A also showed synergism with MINO and FOM in anti-MASA activity. Partial synergism was observed with ABPC, GM and VCM. Synergism with ABPC was not detected in anti-MRSA activity. On the other hand, the synergism of compound B with FOM, and the partial synergisms with ABPC, GM and MINO were also found against MRSA. No synergism with ABPC was found against MRSA. These results suggested that compound A and B could possibly reduce the daily administration dose of these antibiotics in the treatment of nosocomial infections, and also reduce the possibility of the occurrence of nosocomial infections caused by VRE and/or MRSA. PMID:18839630
Sakagami, Yoshikazu; Komemushi, Sadao; Tsukamoto, Goro; Kondo, Hirosato; Yoshikawa, Akiko; Muraoka, Osamu
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??g/ml. The extract of Dorstenia psilurus was the most active when tested in the presence of an efflux pump inhibitor, phenylalanine Arginine-?- Naphtylamide (PA?N), 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.
In the Dominican Republic, poultry consumption per capita is greater than 34 kg of poultry meat per year. However, antibiotics, specifically the quinolone group, may be overused and can result in residues in the poultry meat. These residues are of concern because consumers may have allergies to antibiotics and antibiotic-resistant bacteria can develop from overuse of antibiotics in production. Little is known concerning this issue specifically for Santiago Province in the Dominican Republic. Thus, the main purpose of this research was to evaluate the incidence of residual quinolones in poultry meat and determine whether any residues detected were higher than the residue maximum limits (100 ?g/kg) established by food industry authorities, including the U.S. Food and Drug Administration and European Food Safety Authority. A total of 135 samples of chicken breast were taken from different retail meat centers in the nine municipalities of Santiago Province (Santiago, Tamboril, Sabana Iglesia, Villa Bisonó, Puńal, Villa González, Licey, Jánico, and San José De Las Matas) and were analyzed using the Equinox test (Immunotec, Swanton, VT). Of the 135 samples analyzed, 50% from Sabana Iglesia, 20% from Licey, 20% from San Jose De Las Matas, and 6.25% from Santiago contained residues of quinolones higher than the residue maximum limits. No quinolone residues were detected in samples obtained from Janico, Punal, Tamboril, Villa Bisono, or Villa Gonzalez. The results of this investigation suggest that some poultry meat sold for human consumption in Santiago Province of the Dominican Republic contains quinolone residues and may represent a health risk to some consumers. PMID:23433388
Silfrany, R O; Caba, R E; Solís de Los Santos, F; Hanning, I
Osteomyelitis has been traditionally treated by the combination of long-term antibiotic therapies and surgical removal of diseased tissue. The multifunctional material was developed in this study with the aim to improve this therapeutic approach by: (a) enabling locally delivered and sustained release of antibiotics at a tunable rate, so as to eliminate the need for repetitive administration of systemically distributed antibiotics; and (b) controllably dissolving itself, so as to promote natural remineralization of the portion of bone lost to disease. We report hereby on the effect of previously synthesized calcium phosphates (CAPs) with tunable solubilities and drug release timescales on bacterial and osteoblastic cell cultures. All CAP powders exhibited satisfying antibacterial performance against Staphylococcus aureus, the main causative agent of osteomyelitis. Still, owing to its highest drug adsorption efficiency, the most bacteriostatically effective phase was amorphous CAP with the minimal inhibitory concentration of less than 1 mg/mL. At the same time, the positive cell response and osteogenic effect of the antibiotic-loaded CAP particles was confirmed in vitro for all the sparsely soluble CAP phases. Adsorption of the antibiotic onto CAP particles reversed the deleterious effect that the pure antibiotic exerted on the osteogenic activity of the osteoblastic cells. The simultaneous osteogenic and antimicrobial performance of the material developed in this study, altogether with its ability to exhibit sustained drug release, may favor its consideration as a material base for alternative therapeutic approaches to prolonged antibiotic administration and surgical debridement typically prescribed in the treatment of osteomyelitis. PMID:23115128
Uskokovi?, Vuk; Desai, Tejal A
Bacteria growing in vivo multiply much more slowly than in vitro. If the bactericidal activity of quinolones may be affected by an increase in generation time (g) was studied in batch cultures as well as under the well-controlled conditions of a continuous-flow culture. By limiting the nutrient supply, generation times were lengthened from approximately 0.45 to 1.5 h up to
A. Dalhoff; S. Matutat; U. Ullmann
Four novel mononuclear Pd(II) complexes have been synthesized with the biologically active Schiff base ligands (L1-L4) derived from 3-amino-2-methyl-4(3H)-quinazolinone. The structure of the complexes has been proposed by elemental analysis, molar conductance, IR, 1H NMR, mass, UV-Vis spectrometric and thermal studies. The investigation of interaction of the complexes with calf thymus DNA (CT-DNA) has been performed with absorption and fluorescence spectroscopic studies. The nuclease activity was done using pUC19 supercoiled DNA by gel-electrophoresis. All the ligands and their Pd(II) complexes have also been screened for their antibacterial activity by discolor diffusion technique.
Prasad, Kollur Shiva; Kumar, Linganna Shiva; Chandan, Shivamallu; Naveen Kumar, R. M.; Revanasiddappa, Hosakere D.
Four novel mononuclear Pd(II) complexes have been synthesized with the biologically active Schiff base ligands (L1-L4) derived from 3-amino-2-methyl-4(3H)-quinazolinone. The structure of the complexes has been proposed by elemental analysis, molar conductance, IR, (1)H NMR, mass, UV-Vis spectrometric and thermal studies. The investigation of interaction of the complexes with calf thymus DNA (CT-DNA) has been performed with absorption and fluorescence spectroscopic studies. The nuclease activity was done using pUC19 supercoiled DNA by gel-electrophoresis. All the ligands and their Pd(II) complexes have also been screened for their antibacterial activity by discolor diffusion technique. PMID:23416915
Prasad, Kollur Shiva; Kumar, Linganna Shiva; Chandan, Shivamallu; Naveen Kumar, R M; Revanasiddappa, Hosakere D
Streptococci are a group of Gram-positive bacteria which are responsible for causing many diverse diseases in humans and other animals worldwide. The high prevalence of resistance of these bacteria to current antibacterial drugs is an alarming problem for the scientific community. The battle against streptococci by using antimicrobial chemotherapies will depend on the design of new chemicals with high inhibitory activity, having also as low toxicity as possible. Multi-target approaches based on quantitative-structure activity relationships (mt-QSAR) have played a very important role, providing a better knowledge about the molecular patterns related with the appearance of different pharmacological profiles including antimicrobial activity. Until now, almost all mt-QSAR models have considered the study of biological activity or toxicity separately. In the present study, we develop by the first time, a unified multitasking (mtk) QSAR model for the simultaneous prediction of anti-streptococci activity and toxic effects against biological models like Mus musculus and Rattus norvegicus. The mtk-QSAR model was created by using artificial neural networks (ANN) analysis for the classification of compounds as positive (high biological activity and/or low toxicity) or negative (otherwise) under diverse sets of experimental conditions. Our mtk-QSAR model, correctly classified more than 97% of the cases in the whole database (more than 11,500 cases), serving as a promising tool for the virtual screening of potent and safe anti-streptococci drugs. PMID:23582445
Speck-Planche, Alejandro; Kleandrova, Valeria V; Cordeiro, M N D S
Mutations in the DNA gyrase GyrA2GyrB2 complex are associated with resistance to quinolones in Mycobacterium tuberculosis. As fluoroquinolones are being used increasingly in the treatment of tuberculosis, we characterized several multidrug-resistant clinical isolates of M. tuberculosis carrying mutations in the genes encoding the GyrA or GyrB subunits associated with quinolone resistance or hypersusceptibility. In addition to the reported putative quinolone resistance mutations in GyrA, i.e., A90V, D94G, and D94H, we found that the GyrB N510D mutation was also associated with ofloxacin resistance. Surprisingly, several isolates bearing a novel combination of gyrA T80A and A90G changes were hypersusceptible to ofloxacin. M. tuberculosis GyrA and GyrB subunits (wild type [WT] and mutants) were overexpressed in Escherichia coli, purified to homogeneity, and used to reconstitute highly active gyrase complexes. Mutant proteins were produced similarly from engineered gyrA and gyrB alleles by mutagenesis. MICs, enzyme inhibition, and drug-induced DNA cleavage were determined for moxifloxacin, gatifloxacin, ofloxacin, levofloxacin, and enoxacin. Mutant gyrase complexes bearing GyrA A90V, D94G, and D94H and GyrB N510D were resistant to quinolone inhibition (MICs and 50% inhibitory concentrations [IC50s] at least 3.5-fold higher than the concentrations for the WT), and all, except the GyrB mutant, were less efficiently trapped as a quinolone cleavage complex. In marked contrast, gyrase complexes bearing GyrA T80A or A90G were hypersusceptible to the action of many quinolones, an effect that was reinforced for complexes bearing both mutations (MICs and IC50s up to 14-fold lower than the values for the WT). This is the first detailed enzymatic analysis of hypersusceptibility and resistance in M. tuberculosis.
Aubry, Alexandra; Veziris, Nicolas; Cambau, Emmanuelle; Truffot-Pernot, Chantal; Jarlier, Vincent; Fisher, L. Mark
We show that quinolone resistance in Helicobacter pylori has reached an alarming level in Germany. Our data suggest that the use of quinolones requires prior antimicrobial susceptibility testing, especially for isolates from patients who have already undergone previous unsuccessful eradication treatments, and also underline the further need for surveillance studies to monitor antibiotic resistance in H. pylori.
Glocker, Erik; Stueger, Hans-Peter; Kist, Manfred
The treatment of infections caused by bacteria resistant to the vast majority of antibiotics is a challenge worldwide. Antimicrobial peptides (APs) make up the front line of defense in those areas exposed to microorganisms, and there is intensive research to explore their use as new antibacterial agents. On the other hand, it is known that subinhibitory concentrations of antibiotics affect the expression of numerous bacterial traits. In this work we evaluated whether treatment of bacteria with subinhibitory concentrations of quinolones may alter the sensitivity to APs. A 1-h treatment of Klebsiella pneumoniae with 0.25× the MIC of ciprofloxacin rendered bacteria more sensitive to polymyxins B and E, human neutrophil defensin 1, and ?-defensin 1. Levofloxacin and nalidixic acid at 0.25× the MICs also increased the sensitivity of K. pneumoniae to polymyxin B, whereas gentamicin and ceftazidime at 0.25× the MICs did not have such an effect. Ciprofloxacin also increased the sensitivities of K. pneumoniae ciprofloxacin-resistant strains to polymyxin B. Two other pathogens, Pseudomonas aeruginosa and Haemophilus influenzae, also became more sensitive to polymyxins B and E after treatment with 0.25× the MIC of ciprofloxacin. Incubation with ciprofloxacin did not alter the expression of the K. pneumoniae loci involved in resistance to APs. A 1-N-phenyl-naphthylamine assay showed that ciprofloxacin and levofloxacin increased the permeabilities of the K. pneumoniae and P. aeruginosa outer membranes, while divalent cations antagonized this action. Finally, we demonstrated that ciprofloxacin and levofloxacin increased the binding of APs to the outer membrane by using dansylated polymyxin B.
Campos, Miguel A.; Morey, Pau; Bengoechea, Jose A.
The in vitro antimicrobial activities of oxolinic acid, flumequine, sarafloxacin, enrofloxacin, and oxytetracycline against strains of bacteria pathogenic to fish (Aeromonas salmonicida subsp. salmonicida, atypical A. salmonicida, Vibrio salmonicida, Vibrio anguillarum, and Yersinia ruckeri) were determined at two different incubation temperatures, 4 and 15 degrees C, by a drug microdilution method. The main objective of the study was to examine the effect of incubation temperature on the in vitro activities of 4-quinolones and oxytetracycline against these bacteria. When tested against A. salmonicida subsp. salmonicida, all of the quinolones examined had MICs two- to threefold higher at 4 degrees C than at 15 degrees C. Similarly, 1.5- to 2-fold higher MICs were recorded for all of the quinolones except sarafloxacin at 4 degrees C than at 15 degrees C when the drugs were tested against V. salmonicida. In contrast to those of the quinolones, the MICs of oxytetracycline were two- to eightfold lower at 4 degrees C than at 15 degrees C against all of the bacterial species tested. Of the antimicrobial agents tested against the bacterial species included in the study, enrofloxacin was the most active and oxytetracycline was the least active. Sarafloxacin was slightly more active than flumequine and oxolinic acid, especially against oxolinic acid-resistant A. salmonicida subsp. salmonicida strains.
Martinsen, B; Oppegaard, H; Wichstr?m, R; Myhr, E
As part of Meropenem Yearly Susceptibility Test Information Collection/USA Surveillance Programme, we monitored the occurrence of quinolone resistance in Escherichia coli over a 10-year period. A total of 271 E. coli isolates from our institution were tested over a 10-year period. Screening for quinolone resistance (qnr) gene was performed. A decline in susceptibility of E. coli isolates to quinolones and aminoglycosides was noted over the 10-year span (P < 0.0001), which was significantly reduced compared with the average susceptibility of all sites. Introduction of quinolone prophylaxis has led to a significant decline in susceptibility of E. coli to all quinolones. The organisms remain susceptible to carbapenems, cefepime, and piperacillin/tazobactam. Periodic surveillance allows for detection of resistance patterns and adjustment of empiric antibiotic choice in patients at high risk for infection. PMID:20471765
Mihu, Coralia N; Rhomberg, Paul R; Jones, Ronald N; Coyle, Elizabeth; Prince, Randall A; Rolston, Kenneth V
Seventeen qnr-containing transconjugants were constructed with azide-resistant Escherichia coli J53 as the recipient, and the MICs of 12 quinolones were tested by agar dilution methods. Sitafloxacin, BAYy3118, and premafloxacin had higher activity in vitro than ciprofloxacin against transconjugants and donors containing qnr. The donors had higher quinolone MICs than the transconjugants.
Wang, Minggui; Sahm, Daniel F.; Jacoby, George A.; Zhang, Yingyuan; Hooper, David C.
Seventeen qnr-containing transconjugants were constructed with azide-resistant Escherichia coli J53 as the recipient, and the MICs of 12 quinolones were tested by agar dilution methods. Sitafloxacin, BAYy3118, and premafloxacin had higher activity in vitro than ciprofloxacin against transconjugants and donors containing qnr. The donors had higher quinolone MICs than the transconjugants. PMID:15047552
Wang, Minggui; Sahm, Daniel F; Jacoby, George A; Zhang, Yingyuan; Hooper, David C
Agar dilution MIC determination was used to compare the activity of DK-507k with those of ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, sitafloxacin, amoxicillin, cefuroxime, erythromycin, azithromycin, and clarithromycin against 113 penicillin-susceptible, 81 penicillin-intermediate, and 67 penicillin-resistant pneumococci (all quinolone susceptible). DK-507k and sitafloxacin had the lowest MICs of all quinolones against quinolone-susceptible strains (MIC at which 50% of isolates were inhibited [MIC50] and MIC90 of both, 0.06 and 0.125 microg/ml, respectively), followed by moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. MICs of beta-lactams and macrolides rose with those of penicillin G. Against 26 quinolone-resistant pneumococci with known resistance mechanisms, DK-507k and sitafloxacin were also the most active quinolones (MICs, 0.125 to 1.0 microg/ml), followed by moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. Mutations in quinolone resistance-determining regions of quinolone-resistant strains were in the usual regions of the parC and gyrA genes. Time-kill testing showed that both DK-507k and sitafloxacin were bactericidal against all 12 quinolone-susceptible and -resistant strains tested at twice the MIC at 24 h. Serial broth passages in subinhibitory concentrations of 10 strains for a minimum of 14 days showed that development of resistant mutants (fourfold or greater increase in the original MIC) occurred most rapidly for ciprofloxacin, followed by moxifloxacin, DK-507k, gatifloxacin, sitafloxacin, and levofloxacin. All parent strains demonstrated a fourfold or greater increase in initial MIC in <50 days. MICs of DK-507k against resistant mutants were lowest, followed by those of sitafloxacin, moxifloxacin, gatifloxacin, ciprofloxacin, and levofloxacin. Four strains were subcultured in subinhibitory concentrations of each drug for 50 days: MICs of DK-507k against resistant mutants were lowest, followed by those of sitafloxacin, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. Exposure to DK-507k and sitafloxacin resulted in mutations, mostly in gyrA. PMID:14638489
Browne, Frederick A; Bozdogan, Bülent; Clark, Catherine; Kelly, Linda M; Ednie, Lois; Kosowska, Klaudia; Dewasse, Bonifacio; Jacobs, Michael R; Appelbaum, Peter C
The macromolecular synthesis assay was optimized in both S. aureus and E. coli imp and used to define patterns of inhibition of DNA, RNA, protein, and cell wall biosynthesis of several drug classes. The concentration of drug required to elicit pathway inhibition differed among the antimicrobial agents tested, with inhibition detected at concentrations significantly below the minimum inhibitory concentration (MIC) for tedizolid; within 4-fold of the MIC for ciprofloxacin, cefepime, vancomycin, tetracycline, and chloramphenicol; and significantly above the MIC for rifampicin and kanamycin. In a DNA gyrase/topoisomerase IV structure-based drug design optimization program, the assay rapidly identified undesirable off-target activity within certain chemotypes, altering the course of the program to focus on the series that maintained on-target activity. PMID:23686103
Cunningham, Mark L; Kwan, Bryan P; Nelson, Kirk J; Bensen, Daniel C; Shaw, Karen J
Summary: Although plasmid-mediated quinolone resistance (PMQR) was thought not to exist before its discovery in 1998, the past decade has seen an explosion of research characterizing this phenomenon. The best-described form of PMQR is determined by the qnr group of genes. These genes, likely originating in aquatic organisms, code for pentapeptide repeat proteins. These proteins reduce susceptibility to quinolones by protecting the complex of DNA and DNA gyrase or topoisomerase IV enzymes from the inhibitory effect of quinolones. Two additional PMQR mechanisms were recently described. aac(6?)-Ib-cr encodes a variant aminoglycoside acetyltransferase with two amino acid alterations allowing it to inactivate ciprofloxacin through the acetylation of its piperazinyl substituent. oqxAB and qepA encode efflux pumps that extrude quinolones. All of these genes determine relatively small increases in the MICs of quinolones, but these changes are sufficient to facilitate the selection of mutants with higher levels of resistance. The contribution of these genes to the emergence of quinolone resistance is being actively investigated. Several factors suggest their importance in this process, including their increasing ubiquity, their association with other resistance elements, and their emergence simultaneous with the expansion of clinical quinolone resistance. Of concern, these genes are not yet being taken into account in resistance screening by clinical microbiology laboratories.
Strahilevitz, Jacob; Jacoby, George A.; Hooper, David C.; Robicsek, Ari
Most Aeromonas strains isolated from two European rivers were previously found to be resistant to nalidixic acid. In order to elucidate the mechanism of this resistance, 20 strains of Aeromonas caviae (n = 10), A. hydrophila (n = 5), and A. sobria (n = 5) complexes, including 3 reference strains and 17 environmental isolates, were investigated. Fragments of the gyrA, gyrB, parC, and parE genes encompassing the quinolone resistance-determining regions (QRDRs) were amplified by PCR and sequenced. Results obtained for the six sensitive strains showed that the GyrA, GyrB, ParC, and ParE QRDR fragments of Aeromonas spp. were highly conserved (?96.1% identity), despite some genetic polymorphism; they were most closely related to those of Vibrio spp., Pseudomonas spp., and members of the family Enterobacteriaceae (72.4 to 97.1% homology). All 14 environmental resistant strains carried a point mutation in the GyrA QRDR at codon 83, leading to the substitution Ser-83?Ile (10 strains) or Ser-83?Arg. In addition, seven strains harbored a mutation in the ParC QRDR either at position 80 (five strains), generating a Ser-80?Ile (three strains) or Ser-80?Arg change, or at position 84, yielding a Glu-84?Lys modification. No amino acid alterations were discovered in the GyrB and ParE QRDRs. Double gyrA-parC missense mutations were associated with higher levels of quinolone resistance compared with the levels associated with single gyrA mutations. The most resistant strains probably had an additional mechanism(s) of resistance, such as decreased accumulation of the drugs. Our data suggest that, in mesophilic Aeromonas spp., as in other gram-negative bacteria, gyrase and topoisomerase IV are the primary and secondary targets for quinolones, respectively.
Goni-Urriza, Marisol; Arpin, Corinne; Capdepuy, Michele; Dubois, Veronique; Caumette, Pierre; Quentin, Claudine
The activities of BMS-284576, clinafloxacin, moxifloxacin, sitafloxacin, trovafloxacin, imipenem, cefoxitin, and clindamycin against 589 Bacteroides fragilis group isolates were determined. The activity of BMS-284576 was comparable to that of trovafloxacin. Sitafloxacin and clinafloxacin were the most active quinolones, and moxifloxacin was the least active. B. fragilis was the most susceptible of the species, and Bacteroides vulgatus was the most resistant. Association of specific antibiotic resistance with Bacteroides species was noted for all quinolones.
Snydman, D. R.; Jacobus, N. V.; McDermott, L. A.; Ruthazer, R.; Goldstein, E.; Finegold, S.; Harrell, L.; Hecht, D. W.; Jenkins, S.; Pierson, C.; Venezia, R.; Rihs, J.; Gorbach, S. L.
Nalidixic acid and two recently synthetized 4-quinolones eliminated F'lac and R-plasmids from E. coli at concentrations of one half or one quarter of the minimum inhibitory concentration (MIC). Two of the three plasmids tested were cured by all derivatives, although with different frequencies. Pefloxacin was the most effective compound compared with the other quinolones and nalidixic acid the least active. PMID:3066515
Selan, L; Scazzocchio, F; Oliva, B; Schippa, S; Allocati, N; Renzini, G
The interaction between pefloxacin, ciprofloxacin, norfloxacin, and ofloxacin and biofilms formed by Staphylococcus epidermidis (20 clinical isolates) was studied. In the presence of 1\\/2-MIC and 1\\/8-MIC of quinolones, the optical density of the biofilms was reduced to 22–24% and 65–74% of the controls, respectively. Treatment of preformed biofilms with quinolones in concentrations ranging from 12.5 ?g\\/ml to 400 ?g\\/mL caused
Mahmoud Yassien; Nancy Khardori
High-level resistance to quinolones has previously been shown to occur in Campylobacter spp. both in vitro and in patients treated with quinolones. We have selected isolates that are resistant to quinolones by plating cells from a susceptible C. jejuni strain, UA535, on medium containing nalidixic acid at 32 micrograms/ml. Fluctuation analysis indicated that resistance occurred by mutation at a frequency of 5 x 10(-8) per cell plated. Unlike what is observed with other gram-negative organisms, the nalidixic acid-resistant mutants demonstrated high-level cross-resistance (MIC, greater than or equal to 4 micrograms/ml) to newer quinolones, including ciprofloxacin, norfloxacin, and temafloxacin, yet remained susceptible to coumermycin A1 and several other unrelated antibiotics. Mutants with an identical resistance phenotype could also be selected from UA535 with ciprofloxacin and norfloxacin at a similar frequency. To study the mechanism of quinolone resistance, DNA gyrases were purified from C. jejuni UA535 and two resistant mutants by heparin-agarose and novobiocin-Sepharose chromatography. After the respective enzyme concentrations were adjusted to equivalent units of activity in the DNA supercoiling reaction, the DNA gyrases from the resistant mutants were found to be 100-fold less susceptible than the wild-type enzyme to inhibition by quinolones. Subunit switching experiments with purified A and B subunits from the wild type and one of the quinolone-resistant mutants indicated that an alteration in the A subunit was responsible for resistance. These results show that a single-step mutation can occur in vitro in the gene encoding DNA gyrase in C. jejuni, producing clinically relevant levels of resistance to the newer quinolones. Images
Gootz, T D; Martin, B A
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
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
Eradication rates in first-line Helicobacter pylori therapy have been declining over the last decades, mainly due to increasing resistance against the recommended antibiotics clarithromycin and metronidazole. Thus, there is a need to evaluate novel regimens and substances to offer effective alternative treatment strategies. New generation quinolones, like levofloxacin and moxifloxacin, exhibit a broad-spectrum activity against various Gram-positive and Gram-negative strains and are mostly well tolerated. Based on a large number of studies, quinolones have been introduced in second-line and rescue treatment and are recommended for these indications in current guidelines. Various studies have investigated alternative strategies for first-line treatment including quinolone-based regimens. In the context of increasing resistance rates of Helicobacter pylori against quinolones some risks and benefits have to be considered when using quinolones as a first-line strategy. Besides numerous studies investigating levofloxacin and moxifloxacin there are some promising results for the new substance sitafloxacin, which might overcome primary resistance of Helicobacter pylori against conventional quinolones. PMID:21811951
Krasz, S; Miehlke, S; Berning, M; Morgner, A; Labenz, J
As novel and drug-resistant bacterial strains continue to present an emerging health threat, the development of new antibacterial agents is critical. This includes making improvements to existing antibacterial scaffolds as well as identifying novel ones. ...
G. Tawa M. D. AbdulHameed N. Singh R. Liu S. Chaudhury
Nitroxoline has been reduced at the mercury electrode in buffered solutions (pH 2-11) in two irreversible cathodic steps. The first step was attributed to reduction of -NO(2) group to the hydroxylamine stage and the second one to reduction-saturation of the C=N double bond. DC-polarographic and various adsorptive stripping voltammetric methods were developed for determination of nitroxoline in bulk form. Limits of quantitation of 1.02×10(-6), 3.05×10(-8), 9.01×10(-9), and 9.12×10(-10)M nitroxoline were achieved by means of the developed DC-polarography, differential-pulse-, linear-sweep-, and square-wave-adsorptive cathodic stripping voltammetric methods, respectively. All these electroanalytical methods were successfully applied for determination of nitroxoline in its Nibiol(®) tablets. While only the developed adsorptive stripping voltammetry methods were successfully applied for determination of the drug in spiked human serum and for pharmacokinetic studies in real human plasma. The analysis was carried out without interference from common excipients and without the necessity for prior extraction or interaction with any reagent during the analysis. PMID:20833114
Ghoneim, Mohamed M; El-Desoky, Hanaa S; Abdel-Galeil, Mohamed M
Antihistaminics are widely used for various indications during microbial infection. Hence, this paper investigates the antimicrobial activities of 10 antihistaminics belonging to both old and new generations using multiresistant Gram-positive and Gram-negative clinical isolates. The bacteriostatic activity of antihistaminics was investigated by determining their MIC both by broth and agar dilution techniques against 29 bacterial strains. Azelastine, cyproheptadine, mequitazine and promethazine were the most active among the tested drugs. Diphenhydramine and cetirizine possessed weaker activity whereas doxylamine, fexofenadine and loratadine were inactive even at the highest tested concentration (1 mg/ml). The MIC of meclozine could not be determined as it precipitated with the used culture media. The MBC values of antihistaminics were almost identical to the corresponding MIC values. The bactericidal activity of antihistaminics was also studied by the viable count technique in sterile saline solution. Evident killing effects were exerted by mequitazine, meclozine, azelastine and cyproheptadine. Moreover, the dynamics of bactericidal activity of azelastine were studied by the viable count technique in nutrient broth. This activity was found to be concentration-dependant. This effect was reduced on increasing the inoculum size while it was increased on raising the pH. The post-antimicrobial effect of 100 ?g/ml azelastine was also determined and reached up to 3.36 h.
El-Nakeeb, Moustafa A.; Abou-Shleib, Hamida M.; Khalil, Amal M.; Omar, Hoda G.; El-Halfawy, Omar M.
Antihistaminics are widely used for various indications during microbial infection. Hence, this paper investigates the antimicrobial activities of 10 antihistaminics belonging to both old and new generations using multiresistant Gram-positive and Gram-negative clinical isolates. The bacteriostatic activity of antihistaminics was investigated by determining their MIC both by broth and agar dilution techniques against 29 bacterial strains. Azelastine, cyproheptadine, mequitazine and promethazine were the most active among the tested drugs. Diphenhydramine and cetirizine possessed weaker activity whereas doxylamine, fexofenadine and loratadine were inactive even at the highest tested concentration (1 mg/ml). The MIC of meclozine could not be determined as it precipitated with the used culture media. The MBC values of antihistaminics were almost identical to the corresponding MIC values. The bactericidal activity of antihistaminics was also studied by the viable count technique in sterile saline solution. Evident killing effects were exerted by mequitazine, meclozine, azelastine and cyproheptadine. Moreover, the dynamics of bactericidal activity of azelastine were studied by the viable count technique in nutrient broth. This activity was found to be concentration-dependant. This effect was reduced on increasing the inoculum size while it was increased on raising the pH. The post-antimicrobial effect of 100 ?g/ml azelastine was also determined and reached up to 3.36 h. PMID:24031715
El-Nakeeb, Moustafa A; Abou-Shleib, Hamida M; Khalil, Amal M; Omar, Hoda G; El-Halfawy, Omar M
ABT-492 demonstrated potent antibacterial activity against most quinolone-susceptible pathogens. The rank order of potency was ABT-492 > trovafloxacin > levofloxacin > ciprofloxacin against quinolone-susceptible staphylococci, streptococci, and enterococci. ABT-492 had activity comparable to those of trovafloxacin, levofloxacin, and ciprofloxacin against seven species of quinolone-susceptible members of the family Enterobacteriaceae, although it was less active than the comparators against Citrobacter freundii and Serratia marcescens. The activity of ABT-492 was greater than those of the comparators against fastidious gram-negative species, including Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, and Legionella spp. and against Pseudomonas aeruginosa and Helicobacter pylori. ABT-492 was as active as trovafloxacin against Chlamydia trachomatis, indicating good intracellular penetration and antibacterial activity. In particular, ABT-492 was more active than trovafloxacin and levofloxacin against multidrug-resistant Streptococcus pneumoniae, including strains resistant to penicillin and macrolides, and H. influenzae, including ?-lactam-resistant strains. It retained greater in vitro activity than the comparators against S. pneumoniae and H. influenzae strains resistant to other quinolones due to amino acid alterations in the quinolone resistance-determining regions of the target topoisomerases. ABT-492 was a potent inhibitor of bacterial topoisomerases, and unlike the comparators, DNA gyrase and topoisomerase IV from either Staphylococcus aureus or Escherichia coli were almost equally sensitive to ABT-492. The profile of ABT-492 suggested that it may be a useful agent for the treatment of community-acquired respiratory tract infections, as well as infections of the urinary tract, bloodstream, and skin and skin structure and nosocomial lung infections.
Nilius, Angela M.; Shen, Linus L.; Hensey-Rudloff, Dena; Almer, Laurel S.; Beyer, Jill M.; Balli, Darlene J.; Cai, Yingna; Flamm, Robert K.
ABT-492 demonstrated potent antibacterial activity against most quinolone-susceptible pathogens. The rank order of potency was ABT-492 > trovafloxacin > levofloxacin > ciprofloxacin against quinolone-susceptible staphylococci, streptococci, and enterococci. ABT-492 had activity comparable to those of trovafloxacin, levofloxacin, and ciprofloxacin against seven species of quinolone-susceptible members of the family Enterobacteriaceae, although it was less active than the comparators against Citrobacter freundii and Serratia marcescens. The activity of ABT-492 was greater than those of the comparators against fastidious gram-negative species, including Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, and Legionella spp. and against Pseudomonas aeruginosa and Helicobacter pylori. ABT-492 was as active as trovafloxacin against Chlamydia trachomatis, indicating good intracellular penetration and antibacterial activity. In particular, ABT-492 was more active than trovafloxacin and levofloxacin against multidrug-resistant Streptococcus pneumoniae, including strains resistant to penicillin and macrolides, and H. influenzae, including beta-lactam-resistant strains. It retained greater in vitro activity than the comparators against S. pneumoniae and H. influenzae strains resistant to other quinolones due to amino acid alterations in the quinolone resistance-determining regions of the target topoisomerases. ABT-492 was a potent inhibitor of bacterial topoisomerases, and unlike the comparators, DNA gyrase and topoisomerase IV from either Staphylococcus aureus or Escherichia coli were almost equally sensitive to ABT-492. The profile of ABT-492 suggested that it may be a useful agent for the treatment of community-acquired respiratory tract infections, as well as infections of the urinary tract, bloodstream, and skin and skin structure and nosocomial lung infections. PMID:14506039
Nilius, Angela M; Shen, Linus L; Hensey-Rudloff, Dena; Almer, Laurel S; Beyer, Jill M; Balli, Darlene J; Cai, Yingna; Flamm, Robert K
The antibacterial activity of a new 7-dimethylpyridinyl quinolone, WIN 57273, was assessed by using in vitro and in vivo models. Agar inclusion and broth dilution in vitro tests revealed broad-spectrum activity against gram-positive and selected gram-negative organisms, with the greatest potency observed against the staphylococci. The MIC for 90% of coagulase-positive strains tested (MIC90) was less than or equal to 0.002 micrograms/ml; for the coagulase-negative strains the MIC90 was 0.008 micrograms/ml. Against enterococci the MIC90 was 0.06 micrograms/ml, with comparable activity observed against group A and group B streptococci as well as against the pneumococci. In general, the MIC90s for the gram-negative bacteria were less than or equal to 1 micrograms/ml. Exceptions were Serratia marcescens (MIC90, 16 micrograms/ml), Citrobacter freundii (MIC90, 4 micrograms/ml), and Pseudomonas aeruginosa (MIC90, 8 micrograms/ml). The greatest potency was observed against Haemophilus spp. and Neisseria spp., with MIC90s of 0.06 and 0.016 micrograms/ml, respectively. Broad-spectrum activity was also observed against anaerobes, with MIC90s ranging from 0.125 to 0.5 micrograms/ml among the species tested. The in vivo efficacy was determined by using a murine model by calculating the 50% protective doses against a lethal bacterial infection caused by strains of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The staphylocci were most susceptible, with 50% protective doses for all strains ranging from 0.1 to 0.7 mg/kg. With the exception of the Pseudomonas infection, which was refractory to treatment, animals that were part of the other infection models responded to less than 10 mg/kg. Equivalent activity was seen with the subcutaneous or the oral route of drug administration. WIN 57273 was significantly more potent than ciprofloxacin in treating gram-positive bacterial infections (2- to 20-fold) but was significantly less effective at treating gram-negative bacterial infections (30- to 300-fold).
Sedlock, D M; Dobson, R A; Deuel, D M; Lesher, G Y; Rake, J B
The antibacterial activity of a new 7-dimethylpyridinyl quinolone, WIN 57273, was assessed by using in vitro and in vivo models. Agar inclusion and broth dilution in vitro tests revealed broad-spectrum activity against gram-positive and selected gram-negative organisms, with the greatest potency observed against the staphylococci. The MIC for 90% of coagulase-positive strains tested (MIC90) was less than or equal to 0.002 micrograms/ml; for the coagulase-negative strains the MIC90 was 0.008 micrograms/ml. Against enterococci the MIC90 was 0.06 micrograms/ml, with comparable activity observed against group A and group B streptococci as well as against the pneumococci. In general, the MIC90s for the gram-negative bacteria were less than or equal to 1 micrograms/ml. Exceptions were Serratia marcescens (MIC90, 16 micrograms/ml), Citrobacter freundii (MIC90, 4 micrograms/ml), and Pseudomonas aeruginosa (MIC90, 8 micrograms/ml). The greatest potency was observed against Haemophilus spp. and Neisseria spp., with MIC90s of 0.06 and 0.016 micrograms/ml, respectively. Broad-spectrum activity was also observed against anaerobes, with MIC90s ranging from 0.125 to 0.5 micrograms/ml among the species tested. The in vivo efficacy was determined by using a murine model by calculating the 50% protective doses against a lethal bacterial infection caused by strains of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The staphylocci were most susceptible, with 50% protective doses for all strains ranging from 0.1 to 0.7 mg/kg. With the exception of the Pseudomonas infection, which was refractory to treatment, animals that were part of the other infection models responded to less than 10 mg/kg. Equivalent activity was seen with the subcutaneous or the oral route of drug administration. WIN 57273 was significantly more potent than ciprofloxacin in treating gram-positive bacterial infections (2- to 20-fold) but was significantly less effective at treating gram-negative bacterial infections (30- to 300-fold). PMID:2344163
Sedlock, D M; Dobson, R A; Deuel, D M; Lesher, G Y; Rake, J B
The in vitro activity of DX-619, a new des-F(6)-quinolone, was tested against staphylococci and compared to those of other antimicrobials. DX-619 had the lowest MIC ranges/MIC50s/MIC90s (?g/ml) against 131 Staphylococcus aureus strains (?0.002 to 2.0/0.06/0.5) and 128 coagulase-negative staphylococci (0.004 to 0.25/0.016/0.125). Among strains tested, 76 S. aureus strains and 51 coagulase-negative staphylococci were resistant to ciprofloxacin. DX-619 had the lowest MIC50/MIC90 values against 127 quinolone-resistant staphylococci (0.125/0.5), followed by sitafloxacin (0.5/4), moxifloxacin (2/8), gatifloxacin (4/16), levofloxacin (16/>32), and ciprofloxacin (>32/>32). Raised quinolone MICs were associated with mutations in GyrA (S84L) and single or double mutations in GrlA (S80F or Y; E84K, G, or V) in all S. aureus strains tested. A recent vancomycin-resistant S. aureus (VRSA) strain (Hershey) was resistant to available quinolones and was inhibited by DX-619 at 0.25 ?g/ml and sitafloxacin at 1.0 ?g/ml. Vancomycin (except VRSA), linezolid, ranbezolid, tigecycline, and quinupristin-dalfopristin were active against all strains, and teicoplanin was active against S. aureus but less active against coagulase-negative staphylococci. DX-619 produced resistant mutants with MICs of 1 to >32 ?g/ml after <50 days of selection compared to 16 to >32 ?g/ml for ciprofloxacin, sitafloxacin, moxifloxacin, and gatifloxacin. DX-619 and sitafloxacin were also more active than other tested drugs against selected mutants and had the lowest mutation frequencies in single-step resistance selection. DX-619 and sitafloxacin were bactericidal against six quinolone-resistant (including the VRSA) and seven quinolone-susceptible strains tested, whereas gatifloxacin, moxifloxacin, levofloxacin, and ciprofloxacin were bactericidal against 11, 10, 7, and 5 strains at 4× MIC after 24 h, respectively. DX-619 was also bactericidal against one other VRSA strain, five vancomycin-intermediate S. aureus strains, and four vancomycin-intermediate coagulase-negative staphylococci. Linezolid, ranbezolid, and tigecycline were bacteriostatic and quinupristin-dalfopristin, teicoplanin, and vancomycin were bactericidal against two, eight, and nine strains, and daptomycin and oritavancin were rapidly bactericidal against all strains, including the VRSA. DX-619 has potent in vitro activity against staphylococci, including methicillin-, ciprofloxacin-, and vancomycin-resistant strains.
Bogdanovich, Tatiana; Esel, Duygu; Kelly, Linda M.; Bozdogan, Bulent; Credito, Kim; Lin, Gengrong; Smith, Kathy; Ednie, Lois M.; Hoellman, Dianne B.; Appelbaum, Peter C.
The in vitro activity of DX-619, a new des-F(6)-quinolone, was tested against staphylococci and compared to those of other antimicrobials. DX-619 had the lowest MIC ranges/MIC(50)s/MIC(90)s (microg/ml) against 131 Staphylococcus aureus strains (=0.002 to 2.0/0.06/0.5) and 128 coagulase-negative staphylococci (0.004 to 0.25/0.016/0.125). Among strains tested, 76 S. aureus strains and 51 coagulase-negative staphylococci were resistant to ciprofloxacin. DX-619 had the lowest MIC(50)/MIC(90) values against 127 quinolone-resistant staphylococci (0.125/0.5), followed by sitafloxacin (0.5/4), moxifloxacin (2/8), gatifloxacin (4/16), levofloxacin (16/>32), and ciprofloxacin (>32/>32). Raised quinolone MICs were associated with mutations in GyrA (S84L) and single or double mutations in GrlA (S80F or Y; E84K, G, or V) in all S. aureus strains tested. A recent vancomycin-resistant S. aureus (VRSA) strain (Hershey) was resistant to available quinolones and was inhibited by DX-619 at 0.25 microg/ml and sitafloxacin at 1.0 microg/ml. Vancomycin (except VRSA), linezolid, ranbezolid, tigecycline, and quinupristin-dalfopristin were active against all strains, and teicoplanin was active against S. aureus but less active against coagulase-negative staphylococci. DX-619 produced resistant mutants with MICs of 1 to >32 microg/ml after <50 days of selection compared to 16 to >32 microg/ml for ciprofloxacin, sitafloxacin, moxifloxacin, and gatifloxacin. DX-619 and sitafloxacin were also more active than other tested drugs against selected mutants and had the lowest mutation frequencies in single-step resistance selection. DX-619 and sitafloxacin were bactericidal against six quinolone-resistant (including the VRSA) and seven quinolone-susceptible strains tested, whereas gatifloxacin, moxifloxacin, levofloxacin, and ciprofloxacin were bactericidal against 11, 10, 7, and 5 strains at 4x MIC after 24 h, respectively. DX-619 was also bactericidal against one other VRSA strain, five vancomycin-intermediate S. aureus strains, and four vancomycin-intermediate coagulase-negative staphylococci. Linezolid, ranbezolid, and tigecycline were bacteriostatic and quinupristin-dalfopristin, teicoplanin, and vancomycin were bactericidal against two, eight, and nine strains, and daptomycin and oritavancin were rapidly bactericidal against all strains, including the VRSA. DX-619 has potent in vitro activity against staphylococci, including methicillin-, ciprofloxacin-, and vancomycin-resistant strains. PMID:16048943
Bogdanovich, Tatiana; Esel, Duygu; Kelly, Linda M; Bozdogan, Bülent; Credito, Kim; Lin, Gengrong; Smith, Kathy; Ednie, Lois M; Hoellman, Dianne B; Appelbaum, Peter C
This article reviews perioperative antibacterial prophylaxis, a discrete in-hospital intervention that prevents surgical site infections and reduces the costs of complications and adverse effects of care. Clinical trials have shown that, when used appropriately, prophylactic antibacterial agents are effective and cost effective. Appropriate use requires targeting micro-organisms that are expected to contaminate the operative field; attaining effective drug concentrations in
Dual-targeting properties of the 3-aminopyrrolidyl quinolones, DC159a and sitafloxacin, against DNA gyrase and topoisomerase IV: contribution to reducing in vitro emergence of quinolone-resistant Streptococcus pneumoniae
Objectives: DC-159a (a novel quinolone) and sitafloxacin (DU-6859a) are structurally related quino- lones, bearing a 3-aminopyrrolidyl substitution. We investigated the relationship between the target preferences of these 3-aminopyrrolidyl quinolones, in vitro potencies and emergence of quinolone- resistant mutants in Streptococcus pneumoniae, compared with other quinolones. Methods: MICs, resistance frequencies and mutant prevention concentrations (MPCs) were determined using quinolone-susceptible strains and
Ryo Okumura; Tsuyoshi Hirata; Yoshikuni Onodera; Kazuki Hoshino; Tsuyoshi Otani; Tomoko Yamamoto
A series of novel C-7 quinolyl-substituted enantiomers of ofloxacin were used to determine the stereospecificity of topoisomerase II for the C-11 methyl group in tricyclic quinolones. In all cases, the S isomer was the most active compound against the eukaryotic enzyme. It was approximately 2.2-fold more potent than the R isomer at inhibiting the overall catalytic activity of topoisomerase II (as monitored by DNA relaxation assays). A markedly greater difference in quinolone activity was observed in enzyme-mediated DNA cleavage reactions. While the S enantiomer stimulated nucleic acid breakage approximately 3.5-fold, the R compound did not enhance and, in fact, decreased initial DNA cleavage levels by approximately 50%. The activity of the racemic mixture more closely resembled that of the R enantiomer. In competition experiments, the DNA cleavage-enhancing effects of the S isomer were attenuated by the R compound. Taken together, these latter results indicate that the R enantiomer is an antagonist of S isomer-promoted topoisomerase II-mediated DNA cleavage. Finally, the cytotoxic potential of quinolyl-substituted ofloxacin analogs correlated with the ability to stimulate enzyme-mediated DNA cleavage. Thus, stereochemistry appears to be a governing factor for the potential development of tricyclic quinolones as topoisomerase II-targeted drugs with antineoplastic activity. Images
Froelich-Ammon, S J; McGuirk, P R; Gootz, T D; Jefson, M R; Osheroff, N
A cross-sectional descriptive study among Norwegian nursing homes was conducted in 2003 to examine pharmacoepidemiological characteristics of antibacterials in nursing homes and also to estimate their share of overall antibacterial use in Norway. Antibacterial data were collected for ATC group J01 antibacterials for systemic use, A07AA09 vancomycin and P01AB01 metronidazole in DDDs/y. The amount of drugs principally prescribed for urinary tract infections (UTI) were depicted and used as an indicator for the treatment frequency for UTI in the nursing homes. Prescription of antibacterials in the 133 nursing homes that delivered data varied - from 4 to 44 DDD/100 bed-d. The urinary prophylactic agent, methenamine, represented nearly half of DDDs used, mean 7.3 DDD/100 bed-d. Penicillins with extended spectrum (J01CA) were most frequently used, followed by trimethoprim and sulfonamides (J01E), mean 2.3 and 1.5 DDD/100 bed-d, respectively. On average, 49% of the therapeutic antibacterials were drugs used for UTI, range 12%-88%. In 2003, the nursing home setting purchased an estimated 6% of human antibacterial use in Norway. Nursing homes represent an important share of national human use of antibacterials. The large variation in antibacterial use between facilities underlines the need for increased focus on rational prescribing in nursing homes. PMID:17577815
Blix, Hege Salvesen; Rřed, Jenny; Sti, May Oddrun
The new fluorinated quinolones norfloxacin, ciprofloxacin and pefloxacin were evaluated in urinary infections. Bacteriological cure rates in both uncomplicated and complicated urinary tract infections ranged from 85% to 99%. Clinical cure rates were often lower due to the underlying conditions in the urinary tract. Patients with neurological bladder disease were cured in a relatively high percentage of theirPseudomonas infection after
J. B. J. Boerema
A set of 30 mutants exhibiting reduced production of the phenazine poison pyocyanin were isolated following transposon mutagenesis of Pseudomonas aeruginosa PAO1. The mutants could be subdivided into those with defects in the primary phenazine biosynthetic pathway and those with more pleiotropic defects. The largest set of pleiotropic mutations blocked the production of the extracellular Pseudomonas quinolone signal (PQS), a
Larry A. Gallagher; Susan L. McKnight; Marina S. Kuznetsova; Everett C. Pesci; Colin Manoil
The activities of BMS-284576, clinafloxacin, moxifloxacin, sitafloxacin, trovafloxacin, imipenem, cefoxitin, and clindamycin against 589 Bacteroides fragilis group isolates were determined. The activity of BMS-284576 was comparable to that of trovafloxacin. Sitafloxacin and clinafloxacin were the most active quinolones, and moxifloxacin was the least active. B. fragilis was the most susceptible of the species, and Bacteroides vulgatus was the most resistant.
D. R. Snydman; N. V. Jacobus; L. A. McDermott; R. Ruthazer; E. Goldstein; S. Finegold; L. Harrell; D. W. Hecht; S. Jenkins; C. Pierson; R. Venezia; J. Rihs; S. L. Gorbach
The in vitro activity of the new fluoroquinolone HSR-903 was compared with those of ciprofloxacin, lomefloxacin, sparfloxacin, and levofloxacin. HSR-903 inhibited 90% of methicillin-susceptible and -resistant Staphylococcus aureus (MRSA) clinical isolates at 0.78 and 1.56 microg/ml, respectively, and its activity against MRSA was 16-fold higher than those of sparfloxacin and levofloxacin and 64-fold higher than that of ciprofloxacin. The MICs at which 90% of the isolates are inhibited (MIC90s) of HSR-903 for Streptococcus pyogenes and penicillin G-susceptible and -resistant Streptococcus pneumoniae (PRSP) were 0.10, 0.05, and 0.05 microg/ml, respectively. Against PRSP, the activity of HSR-903 was 4-fold higher than that of sparfloxacin and 32- to 256-fold higher than those of the other quinolones. The MIC90 of HSR-903 for Enterococcus faecalis was 0.20 microg/ml, and HSR-903 was more active than the other quinolones against enterococci. The activity of HSR-903 against members of the family Enterobacteriaceae and Pseudomonas aeruginosa was roughly similar to that of ciprofloxacin and greater than those of the other quinolones. Against Haemophilus influenzae, Moraxella catarrhalis, and Helicobacter pylori, HSR-903 was the most potent of the quinolones tested. The activity of HSR-903 was not affected by the medium, the inoculum size, or the addition of serum, but decreased under acidic conditions, as did those of the other quinolones tested. HSR-903 exhibited rapid bactericidal action and had a good postantibiotic effect on S. aureus and P. aeruginosa. HSR-903 inhibited supercoiling by DNA gyrase from Escherichia coli, but it was much less active against human topoisomerase II.
Takahashi, Y; Masuda, N; Otsuki, M; Miki, M; Nishino, T
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
White, Anthony R
Background: Resistance to fluoroquinolone drugs is emerging among E. coli causing community acquired urinary tract infections (COMA-UTI).\\u000a \\u000a \\u000a \\u000a Objectives: To evaluate demographic and clinical risk factors associated with COMA-UTI due to quinolone-resistant E. coli (QREc).\\u000a \\u000a \\u000a \\u000a Methods: In this case-control study, clinical and demographic data from 300 COMA-UTI due to E. coli (including 150 QREc) were analyzed.\\u000a \\u000a \\u000a \\u000a Results: By univariate analysis QREc was associated to males,
R. Colodner; I. Kometiani; B. Chazan; R. Raz
Chitosan is non-toxic, biocompatible, and biodegradable polysaccharide from renewable resources, known to have inherent antibacterial activity, which is mainly due to its polycationic nature. The combining of all assets of chitosan and its derivatives with the unique properties of electrospun nanofibrous materials is a powerful strategy to prepare new materials that can find variety of biomedical applications. In this article the most recent studies on different approaches for preparation of antibacterial fibrous materials from chitosan and its derivatives such as electrospinning, coating, and electrospinning-electrospraying, loading of drugs or bioactive nanoparticles are summarized. PMID:23754600
Ignatova, Milena; Manolova, Nevena; Rashkov, Iliya
Synthesis of intervenolin, a natural quinolone discovered by screening for selective growth inhibitors of cancer cells cocultured with stromal cells over monocultured cells, was achieved. The synthesis utilized a thiocyanate-isothiocyanate rearrangement and Suzuki-Miyaura coupling to furnish the characteristic substituents, the iminodithiocarbonate moiety, and the geranyl side chain, respectively. In vivo studies showed that intervenolin inhibited tumor tissue growth in model mice. PMID:23594173
Abe, Hikaru; Kawada, Manabu; Inoue, Hiroyuki; Ohba, Shun-ichi; Nomoto, Akio; Watanabe, Takumi; Shibasaki, Masakatsu
A series of quinolone derivatives, containing different heterocyclic amines were prepared. Synthesized compounds were evaluated for their in vitro antimicrobial activities against two Gram-positive bacteria, three Gram-negative bacteria as well as four fungi. All the derivatives showed good activity towards Gram-positive bacteria and less activity towards Gram-negative bacteria. They also showed moderate to comparable activity against Aspergillus niger and Candida albicans and low to moderate antifungal activity against Aspergillus fumigatus and Aspergillus flavus. PMID:23611733
Panda, Siva S; Jain, Subhash C
With more than 100 antibacterial drugs at our disposal in the 1980’s, the problem of bacterial infection was considered solved. Today, however, most hospital infections are insensitive to several classes of antibacterial drugs, and deadly strains of Staphylococcus aureus resistant to vancomycin – the last resort antibiotic – have recently begin to appear. Other life-threatening microbes, such as Enterococcus faecalis
Chantal Abergel; Bruno Coutard; Deborah Byrne; Sabine Chenivesse; Jean-Baptiste Claude; Céline Deregnaucourt; Thierry Fricaux; Celine Gianesini-Boutreux; Sandra Jeudy; Régine Lebrun; Caroline Maza; Cédric Notredame; Olivier Poirot; Karsten Suhre; Majorie Varagnol; Jean-Michel Claverie
Three new carbazole alkaloids, harmandianamines A-C (1-3), together with fifteen known compounds (4-18) were isolated from the twigs of Clausena harmandiana. The structures were elucidated by spectroscopic methods, including UV, IR, NMR, and MS. The antibacterial activity against Escherichia coli TISTR 780, Salmonella typhimurium TISTR 292, Staphylococcus aureus TISTR 1466 and methicillin-resistant S. aureus (MRSA) SK1 of some isolated compounds was also evaluated. Compound 6 exhibited significant antibacterial activity against MRSA SK1 with an MIC value of 0.25 ?g/mL which higher than that of standard drug, vancomycin (MIC value=1 ?g/mL) whereas compounds 14 and 5 showed strong activity with MIC values of 4 and 8 ?g/mL, respectively. Only compound 14 showed strong antibacterial activity against S. aureus TISTR 1466 with an MIC value of 4 ?g/mL. PMID:22579839
Maneerat, Wisanu; Phakhodee, Wong; Ritthiwigrom, Thunwadee; Cheenpracha, Sarot; Promgool, Trinop; Yossathera, Kulsiri; Deachathai, Suwanna; Laphookhieo, Surat
The history of the development of the quinolones is described from the first quinolone, nalidixic acid, via the first 6-fluorinated quinolone norfloxacin, to the latest extended-spectrum fluoroquinolones. The structural modifications made to the basic quinolone and naphthyridone nucleus and to the side chains have allowed improvements to be made such that the next group of fluoroquinolones after norfloxacin, exemplified by
P. C. Appelbaum; P. A. Hunter
Clinical trial of Zoflox, an antimicrobial drug, was performed in complex therapy of elderly outpatients with acute pneumonia complicating acute respiratory viral infection. Among the outpatients there were elderly subjects with hepatic insufficiency. The drug showed to be efficient and safety when used in a middle therapeutic dose of 400 mg twice a day daily for 10-14 days. PMID:23477218
Zueva, L B
We sought to determine whether celecoxib would induce convulsions when coadministered with new quinolone antimicrobial agents in mice. The oral administration of celecoxib (500 mg/kg) alone or in combination with enoxacin (500 mg/kg), lomefloxacin (1000 mg/kg), ciprofloxacin (1000 mg/kg), or levofloxacin (1000 mg/kg) induced no convulsions in mice. In contrast, some nonsteroidal anti-inflammatory drugs (NSAIDs), fenbufen (200 mg/kg), indomethacin (500 mg/kg), and naproxen (500 mg/kg) induced convulsions in combination with the majority of the new quinolones tested. gamma-Aminobutyric acid (GABA)(A) receptor blockade-mediated neuronal excitation is assumed to be involved in these toxic convulsions. Enoxacin (100 microM) and lomefloxacin (100 microM) only slightly reduced [3H]muscimol binding to GABA(A) receptors in mouse whole brain membrane. However, these reductions were markedly enhanced by the addition of fenbufen (100 microM), indomethacin (100 microM), or naproxen (100 microM). Conversely, celecoxib (100 microM) had no apparent effect on [3H]muscimol binding when applied alone or in combination with enoxacin or lomefloxacin. These results suggest that celecoxib may be a more desirable anti-inflammatory agent with respect to drug interactions with new quinolones compared with some conventional NSAIDs. PMID:15659296
Yoshino, Taiji; Noguchi, Masahiro; Okutsu, Hiroko; Kimoto, Aishi; Sasamata, Masao; Miyata, Keiji
BACKGROUND AND OBJECTIVES: Gonococcal fluoroquinolone resistance is now a significant problem in Japan. We generated gonococcal mutants resistant to norfloxacin in vitro from norfloxacin sensitive isolates and analysed the contribution of three known mechanisms of quinolone resistance in Neisseria gonorrhoeae. MATERIALS AND METHODS: Three clinical isolates of N gonorrhoeae susceptible to norfloxacin were exposed to increasing concentrations of norfloxacin. To identify mutations in the gyrA and parC genes of the gonococcal mutants, the quinolone resistance determining regions of the gyrA and parC genes were polymerase chain reaction (PCR) amplified and the PCR products were directly sequenced. Norfloxacin accumulation in the gonococcal cells was also measured. RESULTS: The MICs of norfloxacin for three variants containing a single GyrA mutation were 16-fold higher than that for their parent isolates. A variant showing reduced norfloxacin accumulation in the cells, without mutations in the GyrA or ParC proteins, was also less sensitive to norfloxacin, with a 16-fold increase in the MIC, compared with the parent strain. The MIC of norfloxacin for a variant which contained a single GyrA mutation with reduced norfloxacin accumulation in the cells was 128-fold higher than for the parent strain. A variant containing mutations in both GyrA and ParC proteins with reduced accumulation of norfloxacin in the cells showed a 256-fold increase in the norfloxacin MIC compared with the parent strain. There was no variant containing a ParC mutation without the simultaneous presence of a GyrA mutation. CONCLUSIONS: The results from this study suggest that not only a mutation in the gyrA gene but also reduced drug accumulation in cells contributes to the development of fluoroquinolone a mutation in the gyrA gene contributes to a high level of fluoroquinolone resistance in gonococci with decreases in accumulation in cells having an additional but lesser effect. ???
Tanaka, M.; Sakuma, S.; Takahashi, K.; Nagahuzi, T.; Saika, T.; Kobayashi, I.; Kumazawa, J.
Several quinolones have been shown to have antichlamydial activity in vitro and in vivo. We evaluated the effects of the quinolone CI-960 (Parke-Davis) on primary or repeated chlamydial infection in the monkey salpinx pocket model. The antichlamydial effect was evaluated in the tissues, and we tested for the presence of the organism by culture, immunocytochemical stains, in situ hybridization, and histopathology. An intravenous dosage of 5 mg/kg of body weight produced therapeutic concentrations in plasma (blood sera and pocket fluids) of at least 0.25 microgram/ml at 2 h posttreatment. In monkeys with primary infections, treatment was started 2 days after inoculation and was continued for 7 days. After CI-960 treatment, all animals became culture negative. One of two control animals was culture positive through day 10 postinoculation. In monkeys with repeated infections five inoculations were given within 2 weeks. A 7-day intravenous treatment was started on day 2 postinoculation following the last inoculation. Isolation of Chlamydia trachomatis prior to treatment was positive intermittently for all monkeys. After treatment, isolation of C. trachomatis was negative for all monkeys. In monkeys with both primary and repeated infections, no significant differences were noted in the inflammatory responses in the tissues of treated and untreated animals. All tissues tested were positive by immunoperoxidase staining and/or in situ hybridization. After CI-960 therapy, C. trachomatis organisms were no longer recoverable by cell culture. The persistent finding of chlamydial DNA throughout the observation periods following drug therapy may indicate the presence of dead organisms or viable organisms in an unculturable state. PMID:8381642
Patton, D L; Cosgrove, Y T; Kuo, C C; Campbell, L A
Several quinolones have been shown to have antichlamydial activity in vitro and in vivo. We evaluated the effects of the quinolone CI-960 (Parke-Davis) on primary or repeated chlamydial infection in the monkey salpinx pocket model. The antichlamydial effect was evaluated in the tissues, and we tested for the presence of the organism by culture, immunocytochemical stains, in situ hybridization, and histopathology. An intravenous dosage of 5 mg/kg of body weight produced therapeutic concentrations in plasma (blood sera and pocket fluids) of at least 0.25 microgram/ml at 2 h posttreatment. In monkeys with primary infections, treatment was started 2 days after inoculation and was continued for 7 days. After CI-960 treatment, all animals became culture negative. One of two control animals was culture positive through day 10 postinoculation. In monkeys with repeated infections five inoculations were given within 2 weeks. A 7-day intravenous treatment was started on day 2 postinoculation following the last inoculation. Isolation of Chlamydia trachomatis prior to treatment was positive intermittently for all monkeys. After treatment, isolation of C. trachomatis was negative for all monkeys. In monkeys with both primary and repeated infections, no significant differences were noted in the inflammatory responses in the tissues of treated and untreated animals. All tissues tested were positive by immunoperoxidase staining and/or in situ hybridization. After CI-960 therapy, C. trachomatis organisms were no longer recoverable by cell culture. The persistent finding of chlamydial DNA throughout the observation periods following drug therapy may indicate the presence of dead organisms or viable organisms in an unculturable state. Images
Patton, D L; Cosgrove, Y T; Kuo, C C; Campbell, L A
Sophorolipids (SLs), glycolipids produced by yeasts, have been reported to have immunomodulating activity and to reduce the mortality rate in animal models of sepsis. In the present study, the antibacterial activities of SLs and several derivatives were tested against a selection of standard bacterial isolates using the broth microdilution method. The SL derivatives tested did not show any significant antibacterial activity in vitro when tested at clinically relevant concentrations. Most likely the reported decrease of mortality rate in the rat septic shock model was not secondary to antibacterial activity of SLs. The SLs may be used as anti-inflammatory agents or immunomodulators without affecting the host's bacterial flora. PMID:19201743
Sleiman, Joseph N; Kohlhoff, Stephan A; Roblin, Patricia M; Wallner, Sabine; Gross, Richard; Hammerschlag, Margaret R; Zenilman, Michael E; Bluth, Martin H
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 ?-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 ?-lactamase (TUS/MUS) genes were absent, and resistance due to these genes was ruled out, indicating involvement of other secretion machinery.
Dharne, M.S.; Gupta, A.K.; Rangrez, A.Y.; Ghate, H.V.; Patole, M.S.; Shouche, Y.S.
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.
The mechanism of quinolone resistance in Mycoplasma genitalium remains poorly understood due to difficulties with in vitro culture, especially of clinical isolates. In this study, to confirm the association between mutations in topoisomerases and antimicrobial susceptibilities to quinolones, ciprofloxacin-resistant mutant strains were selected using the cultivable type strain ATCC 33530. Sequence analysis revealed that the mutant strains harbored mutations in topoisomerase IV: Gly81Cys in ParC, Pro261Thr in ParC, or Asn466Lys in ParE. The MICs of all quinolones tested against the mutant strains were 2- to 16-fold higher than those against the wild-type strain. No cross-resistance was observed with macrolides or tetracyclines. We determined the inhibitory activities of quinolones against DNA gyrase and topoisomerase IV in order to investigate the correlation between antimicrobial susceptibility and inhibitory activity against the target enzymes, considered the primary targets of quinolones. Furthermore, using enzymatic analysis, we confirmed that Gly81Cys in the ParC quinolone resistance-determining region (QRDR) contributed to quinolone resistance. This is the first study to isolate quinolone-resistant mutant strains of M. genitalium harboring substitutions in the parC or parE gene in vitro and to measure the inhibitory activities against the purified topoisomerases of M. genitalium.
Takei, Masaya; Kishii, Ryuta; Yasuda, Mitsuru; Deguchi, Takashi
We studied the evolution of resistance to quinolones in Escherichia coli from 1992 to 1997 in Barcelona, Spain. An increasing proportion of quinolone-resistant E. coli (QREC) infections was observed. QREC strains were more common in patients with nosocomial infections but also increased in patients with community- acquired infections (9% in 1992 to 17% in 1996). Seventy (12%) of 572 episodes
JAVIER GARAU; MARIONA XERCAVINS; MONICA RODRIGUEZ-CARBALLEIRA; JOSEP RAMONG OMEZ-VERA; IGNACIO COLL; DOLORS VIDAL; TERESA LLOVET; ANA RUIZ-BREMON
Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus isolates were exposed to subinhibitory MICs of ciprofloxacin, sparfloxacin, gatifloxacin, moxifloxacin, clinafloxacin, and gemifloxacin during a 10-day period. Subculturing led to resistance development, regardless of the initial potencies of the quinolones. None of the quinolones was associated with a significantly slower rate of resistance development.
Boos, Mechthild; Mayer, Susanne; Fischer, Ansgar; Kohrer, Karl; Scheuring, Sibylle; Heisig, Peter; Verhoef, Jan; Fluit, Ad C.; Schmitz, F.-J.
A simple, accurate, precise, and versatile high-performance liquid chromatographic (HPLC) method was developed and validated for the determination of three quinolone antibiotics in Mueller–Hinton broth. The fluoroquinolone agents studied were ciprofloxacin, ofloxacin, and sparfloxacin; other quinolone agents have been identified using this method but not validated in this matrix (levofloxacin, clinafloxacin, temafloxacin, and trovafloxacin). In addition, several other biological growth
David H Wright; Varen K Herman; Frank N Konstantinides; John C Rotschafer
The antibacterial action of chitosan hydroglutamate (CH), chitosan lactate (CL) and chitosan derived from fungal mycelia was examined against both gram?negative and gram?positive bacteria. Plate counts indicated inactivation rates of one? to five?log?cycles within one hour. Fungal chitosan had significantly less antibiotic effect than CH and CL. The antibacterial action of CH and CL was very similar and shown to
N. R. Sudarshan; D. G. Hoover; D. Knorr
The local application of antibiotics is a well-known procedure that has been in successful clinical use for more than 20 years. The most frequently used carrier substance for the antibiotic or other antibacterial substances is polymethylmethacrylate (PMMA). However, because PMMA is not resorbable, as much as 70% of the antibiotic dose is permanently sequestered in the PMMA cement and therefore not available to combat bacterial colonization. Antibacterial coatings of metal implants represent an attractive solution to simplify the local application of an antibacterial substance in fracture care. Several coating technologies have been investigated, involving different carrier materials as well as different antibacterial substances. A fully resorbable coating containing gentamicin sulphate has yielded promising results in animal studies and intramedullary tibial nails with this coating have already been implanted successfully in a few patients. In the future, the main developmental focus for antibacterial coatings for implants will lie in tailoring the release characteristics and the antibacterial substance to minimize the risk of breeding resistant bacterial strains while maximizing the efficacy of the coating. PMID:16651076
Quinolone antibacterials, originally derived from anti-malarial compounds, have been developed through side-chain and nuclear manipulation, notably by piperazine and other mono- or bi-cyclic substitutions at the 7 position (giving anti-pseudomonal activity and greater anti- Gram-negative activity) and fluorination at various sites (giving increased anti-Gram-positive activity). The class has now been in clinical use for 40 years. Increased activity has not
Fluoroquinolone-induced joint/cartilage toxicity has been observed in juvenile animal studies and is species- and dose-specific with canines exhibiting the highest rate of arthralgias. These early observations led to the contraindication of fluoroquinolones in the pediatric population. Despite these recommendations fluoroquinolones continue to be prescribed for select children with difficult-to-treat infections for whom the benefit of quinolone therapy may outweigh the risk of cartilage toxicity. A review of retrospective and prospective safety data of ciprofloxacin-treated children showed that the rates of arthralgia and quinolone-induced cartilage toxicity were low. Episodes of arthralgia were mostly reversible based on published surveillance data in children. Recent data from Bayer's ciprofloxacin clinical trials database found that the incidence of arthralgia in children did not differ between the ciprofloxacin and nonquinolone antimicrobial control groups. The role of fluoroquinolones in the treatment of certain serious infections in children does not appear to be compromised by safety concerns when used appropriately. PMID:14688586
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.
Berning, Marco; Krasz, Susanne; Miehlke, Stephan
There is now substantial evidence that compounds released during host stress directly activate the virulence of certain opportunistic pathogens. Here, we considered that endogenous opioids might function as such compounds, given that they are among the first signals to be released at multiple tissue sites during host stress. We tested the ability of various opioid compounds to enhance the virulence of Pseudomonas aeruginosa using pyocyanin production as a biological readout, and demonstrated enhanced virulence when P. aeruginosa was exposed to synthetic (U-50,488) and endogenous (dynorphin) ?-agonists. Using various mutants and reporter strains of P. aeruginosa, we identified involvement of key elements of the quorum sensing circuitry such as the global transcriptional regulator MvfR and the quorum sensing-related quinolone signaling molecules PQS, HHQ, and HQNO that respond to ?-opioids. The in vivo significance of ?-opioid signaling of P. aeruginosa was demonstrated in mice by showing that dynorphin is released from the intestinal mucosa following ischemia/reperfusion injury, activates quinolone signaling in P. aeruginosa, and enhances the virulence of P. aeruginosa against Lactobacillus spp. and Caenorhabditis elegans. Taken together, these data demonstrate that P. aeruginosa can intercept opioid compounds released during host stress and integrate them into core elements of quorum sensing circuitry leading to enhanced virulence.
Zaborina, Olga; Lepine, Francois; Xiao, Gaoping; Valuckaite, Vesta; Chen, Yimei; Li, Terry; Ciancio, Mae; Zaborin, Alex; Petroff, Elaine; Turner, Jerrold R; Rahme, Laurence G; Chang, Eugene; Alverdy, John C
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
Berning, Marco; Krasz, Susanne; Miehlke, Stephan
Compound 64716, 1-ethyl-4 (1H)-oxo-[1,3]dioxolo[4,5-g]cinnoline-3-carboxylic acid, is a new synthetic antibacterial agent. The antibacterial spectrum of this compound includes gram-negative bacteria that are most frequently isolated from urinary tract infections. Minimal inhibitory concentration values of 64716 for isolates of Escherichia coli and Proteus sp. ranged from 2 to 4 and 2 to 8 ?g/ml, respectively, and the compound was bactericidal at concentrations close to the minimal inhibitory concentration values. In vivo, doses required for successful therapy of experimental mouse infections were comparable to those for nalidixic acid. After oral administration of 40 mg/kg, peak concentrations of this compound in mouse blood reached 19.2 ?g/ml. Within 30 min after doses of 20 mg/kg, bacteriologically active drug concentrations of 64716, nalidixic acid, and oxolinic acid in mouse urine were >1,000, 170, and <1.5 ?g/ml, respectively. Resistant bacteria were not selected when bacteria were exposed to 500 ?g/ml of 64716. Compound 64716 was less bound by human serum proteins than was nalidixic acid. Equivalent antibacterial activity along with superior pharmacological properties of 64716 when compared with nalidixic acid lead to the conclusion that this new compound is a promising antibacterial agent.
Wick, W. E.; Preston, D. A.; White, W. A.; Gordee, R. S.
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.
Stuck, Anna K.; Tauber, Martin G.; Schabel, Maria; Lehmann, Thomas; Suter, Herbert
[Comparison of antimicrobial use density (AUD) of carbapenem antibacterial agents and investigation of the drug susceptibility of Pseudomonas aeruginosa in 3 hospitals in southern Ibaraki Prefecture, Japan].
The optimal use of anti-Pseudomonas agents is an important issue in the prevention of a tolerance against Pseudomonas aeruginosa. We evaluated the effect of antimicrobial use density (AUD) of carbapenem on drug susceptibility. The AUD of the four carbapenems, imipenem (IPM/CS), panipenem (PAPM/BP), meropenem (MEPM), and biapenem (BIPM), was examined at three hospitals in Ibaraki Prefecture, between April and September 2004. The AUD was calculated using the Defined Daily Doses (DDD) methodology developed by the WHO. A drug susceptibility test was conducted on the 306 Pseudomonas aeruginosa strains randomly collected from clinical specimens at the three hospitals between September and December 2004. In accordance with the standards set by the Clinical and Laboratory Standards Institute (CLSI), minimal inhibitory concentration (MIC) was measured using the broth microdilution method. The results showed that the AUD of carbapenem at the three hospitals tended to be higher than that in other research results in Japan. At one of the three hospitals, the AUD of the PAPM was remarkably high compared to the other carbapenems. Furthermore, P. aeruginosa strains collected at this hospital showed a low susceptibility to carbapenem, and many highly tolerant strains were also observed in this hospital. In order to maintain the susceptibility of Pseudomonas aeruginosa to carbapenem, the overall extent of carbapenem use must be optimal. The use of antimicrobial drugs should be controlled properly at each hospital, in order to prevent excessive use of PAPM/BP from being used over a long period of time. PMID:18709988
Oishi, Tsuyoshi; Hitomi, Shigemi; Kamoshita, Masaharu; Fukue, Hidetaka; Kawahata, Daisuke; Fukutake, Katsuyuki
Bacterial resistance is a major problem in the modern world, stemming in part from the build-up of antibiotics in the environment. Novel molecular approaches that enable an externally triggered increase in antibiotic activity with high spatiotemporal resolution and auto-inactivation are highly desirable. Here we report a responsive, broad-spectrum, antibacterial agent that can be temporally activated with light, whereupon it auto-inactivates on the scale of hours. The use of such a 'smart' antibiotic might prevent the build-up of active antimicrobial material in the environment. Reversible optical control over active drug concentration enables us to obtain pharmacodynamic information. Precisely localized control of activity is achieved, allowing the growth of bacteria to be confined to defined patterns, which has potential for the development of treatments that avoid interference with the endogenous microbial population in other parts of the organism. PMID:24153369
Velema, Willem A; van der Berg, Jan Pieter; Hansen, Mickel J; Szymanski, Wiktor; Driessen, Arnold J M; Feringa, Ben L
To create a drug, nature's blueprints often have to be improved through semisynthesis or total synthesis (chemical postevolution). Selected contributions from industrial and academic groups highlight the arduous but rewarding path from natural products to drugs. Principle modification types for natural products are discussed herein, such as decoration, substitution, and degradation. The biological, chemical, and socioeconomic environments of antibacterial research are dealt with in context. Natural products, many from soil organisms, have provided the majority of lead structures for marketed anti-infectives. Surprisingly, numerous "old" classes of antibacterial natural products have never been intensively explored by medicinal chemists. Nevertheless, research on antibacterial natural products is flagging. Apparently, the "old fashioned" natural products no longer fit into modern drug discovery. The handling of natural products is cumbersome, requiring nonstandardized workflows and extended timelines. Revisiting natural products with modern chemistry and target-finding tools from biology (reversed genomics) is one option for their revival. PMID:16881035
von Nussbaum, Franz; Brands, Michael; Hinzen, Berthold; Weigand, Stefan; Häbich, Dieter
A novel methacrylate monomer containing a quinolone moiety was synthesized and homopolymerized in N,N-dimethylformamide (DMF) by using azobisisobutyronitrile (AIBN) as an initiator. The new monomer was copolymerized with poly(ethylene glycol) methyl ether methacrylate (MPEGMA) in DMF using the same initiator. The monomer, homopolymer, and copolymer were characterized by elemental analysis, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), size exclusion chromatography (SEC), FTIR, (13)C NMR, and (1)H NMR. The antibacterial activities of the monomer as well as polymers were investigated against Staphylococcus aureus and Escherichia coli, which are representative of Gram-positive and Gram-negative bacteria, respectively. All compounds showed excellent antibacterial activities against these two types of bacteria. The antibacterial activities were determined using the shaking flask method, where 25 mg/mL concentrations of each compound were tested against 10(5) CFU/mL bacteria solutions. The number of viable bacteria was calculated by using the spread plate method, where 100 microL of the incubated antibacterial agent in bacteria solutions were spread on agar plates and the number of viable bacteria was counted after 24 h of incubation period at 37 degrees C. PMID:15638560
Dizman, Bekir; Elasri, Mohamed O; Mathias, Lon J
Tuberculosis (TB) constitutes one of the most dangerous and serious health problems around the world. It is a very lethal disease caused by microorganisms of the genus mycobacterium, principally Mycobacterium tuberculosis (MTB) which affects humans. A very active field for the search of more efficient anti-TB chemotherapies is the use in silico methodologies for the discovery of potent anti-TB agents. The battle against MTB by using antimicrobial chemotherapies will depend on the design of new chemicals with high anti-TB activity and low toxicity as possible. Multi-target methodologies focused on quantitative-structure activity relationships (mt-QSAR) have played a very important role for the rationalization of drug design, providing a better understanding about the molecular patterns related with diverse pharmacological profiles including antimicrobial activity. Nowadays, almost all mt-QSAR models have considered the study of biological activity or toxicity separately. In the present study, we develop by the first time, a unified multitasking model based on quantitative-structure biological effect relationships (mtk-QSBER) for the simultaneous prediction of anti-TB activity and toxicity against Mus musculus and Rattus norvegicus. The mtk-QSBER model was created by using linear discriminant analysis (LDA) for the classification of compounds as positive (high biological activity and/or low toxicity) or negative (otherwise) under many experimental conditions. Our mtk-QSBER model, correctly classified more than 90% of the case in the whole database (more than 12,000 cases), serving as a powerful tool for the computer-assisted screening of potent and safe anti-TB drugs. PMID:23376211
Speck-Planche, Alejandro; Kleandrova, Valeria V; Cordeiro, M Natália D S
Comparison of the antibacterial effect of silver sulfadiazine 1%, mupirocin 2%, Acticoat and octenidine dihydrochloride in a full-thickness rat burn model contaminated with multi drug resistant Acinetobacter baumannii.
In this study, our aim is to compare the efficacy of different topical antibacterial agents in a rat model contaminated with a multi drug resistant (MDR) standard Acinetobacter baumannii strain. The study was carried out on 40 Sprague-Dawley rats of 250-300 g each. For the purposes of this study, the rats were divided into 5 groups, with 8 rats in each group: Group 1 control; Group 2 silver sulfadiazine; Group 3 mupirocin; Group 4 Acticoat group; and Group 5 octenidine dihydrochloride group. Following to the formation of the full-thickness burn areas in rats, the MDR A. baumannii standard strain was inoculated into the burned area. The rats in all the groups were sacrificed at the end of the 10th day and subjected to histopathological and microbiological evaluation. In the histopathological evaluation, the lowest inflammatory cell response and bacterial density in the eschar and muscle tissues were observed in the Acticoat group. While these results were found to be statistically significant compared to the silver sulfadiazine group, only the bacterial density in the muscle tissue was found as significant in comparison to the mupirocin and octenidine groups. In the microbiological evaluation, the lowest growth in the muscle tissue culture among all the groups was observed in the Acticoat group. The growth in the eschar tissue culture was significantly lower in the Acticoat and octenidine groups in comparison to the silver sulfadiazine group. At the end of the study, it has been observed that Acticoat was effective both in eschar and muscle, while octenidine was effective in eschar tissues in a rat burn model contaminated with MDR A. baumannii. PMID:22688192
Selçuk, Caferi Tayyar; Durgun, Mustafa; Ozalp, Burhan; Tekin, Alicem; Tekin, Recep; Akçay, Cemal; Alabal?k, Ula?
The aim of the present study was to describe the prescription rate and patterns of antibacterial agents in the Norwegian dog population in relation to time and place during 2004-2008. Prescription data were collected from the Norwegian prescription database (NorPD), whereas an estimate of the dog population was obtained from the Norwegian Kennel Club (NKK). Maps of the geographical prescription rate patterns were generated in the software ArcGIS 9.2. This study indicates an increased usage of antibacterial agents in dogs in Norway during the study period in which antibacterial agents for systemic use and especially the combination amoxicillin and clavulanic acid accounted for the major part. Among antibacterial agents defined as critically important for human medicine, an increase was observed in the prescription rate of quinolones. The geographical prescription rate patterns were stable during the study period, which indicated that the identified increase in usage of antimicrobial agents occurred all over the country, but that there were regional differences in the prescribing behaviour. Prescription data from the NorPD of antibacterial agents to dogs can be used as a basis to perform a risk-based sampling approach to detect emerging antimicrobial resistance in the dog population. PMID:22817637
Kvaale, M K; Grave, K; Kristoffersen, A B; Norström, M
Quinolones are a group of antimicrobial agents that were serendipitously discovered as byproducts of the synthesis of chloroquine. Chemical modifications, such as the addition of fluorine or piperazine, resulted in the synthesis of third- and fourth-generation fluoroquinolones, with broad-spectrum antimicrobial actions against aerobic or anaerobic, Gram-positive or Gram-negative bacteria. The efficacy and consequent widespread use of quinolones and fluoroquinolones has led to a steady global increase in resistance, mediated via gene mutations, alterations in efflux or cell membranes and plasmid-conferred resistance. The first plasmid-mediated quinolone resistance gene, qnrA1, was detected in 1998. Since then, many other genes have been identified and the underlying mechanisms of resistance have been elucidated. This review provides an overview of quinolone resistance, with particular emphasis on plasmid-mediated resistance. PMID:23569126
Guan, Xizhou; Xue, Xinying; Liu, Yuxia; Wang, Jing; Wang, Yong; Wang, Jianxin; Wang, Kaifei; Jiang, Hong; Zhang, Lina; Yang, Bing; Wang, N; Pan, Lei
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. ?-Amyrin acetate (1), n-octacosanol (2), ?-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
Ramasamy, D; Saraswathy, A
The in vitro activities of eight quinolones against 115 coryneform bacteria (20 Corynebacterium jeikeium, 15 Corynebacterium minutissimum, 15 Corynebacterium striatum, 25 Corynebacterium urealyticum, 10 Corynebacterium xerosis, 10 Corynebacterium group ANF-1, 10 Corynebacterium group 12, and 10 Listeria monocytogenes) were determined. The MICs of ciprofloxacin, ofloxacin, and sparfloxacin for 90% of C. jeikeium, C. urealyticum, and C. xerosis isolates tested were > 16 micrograms/ml. Those of BAY Y 3118 and clinafloxacin against these species were 0.5 and 1 to 2 micrograms/ml, respectively. The MICs for 90% of all 115 strains tested were 0.5 microgram/ml for BAY Y 3118, 1 microgram/ml for clinafloxacin, 2 micrograms/ml for E-5068, 4 micrograms/ml for E-5065, and > 16 micrograms/ml for ciprofloxacin, ofloxacin, sparfloxacin, and E-4868. PMID:8092851
Martínez-Martínez, L; Suárez, A I; Ortega, M C; Perea, E J
Pseudomonas aeruginosa is an opportunistic pathogen that causes chronic lung infections in cystic fibrosis patients and is a major source of nosocomial infections. This bacterium controls many virulence factors by using two quorum-sensing systems, las and rhl. The las system is composed of the LasR regulator protein and its cell-to-cell signal, N-(3-oxododecanoyl) homoserine lactone, and the rhl system is composed of RhlR and the signal N-butyryl homoserine lactone. A third intercellular signal, the Pseudomonas quinolone signal (PQS; 2-heptyl-3-hydroxy-4-quinolone), also regulates numerous virulence factors. PQS synthesis requires the expression of multiple operons, one of which is pqsABCDE. Previous experiments showed that the transcription of this operon, and therefore PQS production, is negatively regulated by the rhl quorum-sensing system and positively regulated by the las quorum-sensing system and PqsR (also known as MvfR), a LysR-type transcriptional regulator protein. With the use of DNA mobility shift assays and beta-galactosidase reporter fusions, we have studied the regulation of pqsR and its relationship to pqsA, lasR, and rhlR. We show that PqsR binds the promoter of pqsA and that this binding increases dramatically in the presence of PQS, implying that PQS acts as a coinducer for PqsR. We have also mapped the transcriptional start site for pqsR and found that the transcription of pqsR is positively regulated by lasR and negatively regulated by rhlR. These results suggest that a regulatory chain occurs where pqsR is under the control of LasR and RhlR and where PqsR in turn controls pqsABCDE, which is required for the production of PQS. PMID:15968046
Wade, Dana S; Calfee, M Worth; Rocha, Edson R; Ling, Elizabeth A; Engstrom, Elana; Coleman, James P; Pesci, Everett C
The genotoxicity of quinolone and fluroquinolones was assessed using the micronucleus (MN) test on Vicia faba roots by direct contact exposure to a solid matrix. Plants were exposed to quinolones (nalidixic acid) and fluoroquinolones (ciprofloxacin and enrofloxacin) alone or mixed with artificially contaminated soils. Four different concentrations of each of these antibiotics were tested (0.01, 0.1, 1 and 10mg\\/Kg) for
A. Khadra; E. Pinelli; M. Z. Lacroix; A. Bousquet-Melou; H. Hamdi; G. Merlina; M. Guiresse; M. Hafidi
Summary Quinolones are broad-spectrum antibiotics effective against both Gram-positive and Gram-negative bacteria. Reactive oxygen species (ROS) generated by quinolones may da- mage cell structures and could be a risk to health. The use of vitamin C to reduce such risks may have the opposite effects: vitamin C in the presence of divalent metal ions can induce the Fenton reaction, leading
Myriam Arriaga-Alba; Roberto Rivera-Sánchez; Rocio Flores-Paz; Yessica Dorin Torres-Ramos; Ivonne María Olivares-Corichi; Juan José Hicks
Green synthesis of metallic silver nanoparticles has attracted nowadays and alternative to physical and chemical approaches. In the present study, silver nanoparticles (AgNPs) were synthesized from leaf extract of Mimusops elengi, L. at room temperature. Formation of stable AgNPs at 1mM concentrations of silver nitrate (AgNO3) typically gave spherical shape particles with diameter range from 55 to 83nm. The kinetic properties of particle formation were proportional to the effect of concentration of AgNO3 solution. In order to identify the compounds responsible for the bioreduction of Ag(+) ion and the stabilization of AgNPs produced, the functional group present in Mimusops elengi, L. leaf extract was investigated using FTIR. The formation of nanoparticle was confirmed using the surface plasmon resonance band shown in UV-vis spectrophotometer. The topography and morphology of the particles were determined using scanning electron microscopy. The crystalline nature of nanoparticles was confirmed from the XRD pattern. Furthermore these green synthesized AgNPs were found to show higher antimicrobial efficacy against multi drug resistant clinical isolates. PMID:23563291
Prakash, P; Gnanaprakasam, P; Emmanuel, R; Arokiyaraj, S; Saravanan, M
This study aimed to find the effects of quinolone antibiotics in chicken and beef used in Ankara, Turkey. Total number of 127 chicken and 104 beef meat samples were collected randomly from local markets for analysis. Extraction and determination of quinolones were made by ELISA procedure. One hundred eighteen of 231 (51.1%) examined chicken meat and beef samples were found to contain quinolone antibiotic residue. Among the chicken meat and beef samples, 58 (45.7%) of chicken meat samples and 60 (57.7%) of beef meat samples were positive for quinolones, respectively. The mean levels (±SE) of quinolones were found to be 30.81 ± 0.45 µg/kg and 6.64 ± 1.11 µg/kg in chicken and beef samples, respectively. This study indicated that some chicken and beef meat sold in Ankara contains residues of quinolone antibiotics. PMID:23873571
Er, Buket; Onurdag, Fatma Kaynak; Demirhan, Burak; Ozgacar, Selda Özgen; Oktem, Aysel Bayhan; Abbasoglu, Ufuk
The use of quinolone for treatment of rickettsial diseases remains controversial. Recent clinical studies suggest that quinolone is not as effective as others in patients with rickettsial diseases including scrub typhus, although the mechanism is not well understood. In this study, we evaluated the mutation in gyrA associated with quinolone resistance. We prospectively enrolled scrub typhus patients, collected blood samples and clinical data from October, 2010 to November, 2011. Among the 21 patients enrolled, one initially received ciprofloxacin for 3 days but was switched to doxycycline due to clinical deterioration. We obtained the gyrA gene of Orientia tsutsugamushi from 21 samples (20 Boryong strain, 1 Kato strain) and sequenced the quinolone resistance-determining region. All of 21 samples had the Ser83Leu mutation in the gyrA gene, which is known to be associated with quinolone resistance. This suggests that quinolones may be avoided for the treatment of serious scrub typhus.
Jang, Hee-Chang; Choi, Su-Mi; Jang, Mi-Ok; Ahn, Joon-Hwan; Kim, Uh-Jin; Kang, Seung-Ji; Shin, Jong-Hee; Choy, Hyon E; Jung, Sook-In
The use of quinolone for treatment of rickettsial diseases remains controversial. Recent clinical studies suggest that quinolone is not as effective as others in patients with rickettsial diseases including scrub typhus, although the mechanism is not well understood. In this study, we evaluated the mutation in gyrA associated with quinolone resistance. We prospectively enrolled scrub typhus patients, collected blood samples and clinical data from October, 2010 to November, 2011. Among the 21 patients enrolled, one initially received ciprofloxacin for 3 days but was switched to doxycycline due to clinical deterioration. We obtained the gyrA gene of Orientia tsutsugamushi from 21 samples (20 Boryong strain, 1 Kato strain) and sequenced the quinolone resistance-determining region. All of 21 samples had the Ser83Leu mutation in the gyrA gene, which is known to be associated with quinolone resistance. This suggests that quinolones may be avoided for the treatment of serious scrub typhus. PMID:23678256
Jang, Hee-Chang; Choi, Su-Mi; Jang, Mi-Ok; Ahn, Joon-Hwan; Kim, Uh-Jin; Kang, Seung-Ji; Shin, Jong-Hee; Choy, Hyon E; Jung, Sook-In; Park, Kyung-Hwa
Background Quinolones are potent broad-spectrum bactericidal agents increasingly employed also in resource-limited countries. Resistance to quinolones is an increasing problem, known to be strongly associated with quinolone exposure. We report on the emergence of quinolone resistance in a very remote community in the Amazon forest, where quinolones have never been used and quinolone resistance was absent in 2002. Methods The community exhibited a considerable level of geographical isolation, limited contact with the exterior and minimal antibiotic use (not including quinolones). In December 2009, fecal carriage of antibiotic resistant Escherichia coli was investigated in 120 of the 140 inhabitants, and in 48 animals reared in the community. All fluoroquinolone-resistant isolates were genotyped and characterized for the mechanisms of plasmid- and chromosomal-mediated quinolone resistance. Principal Findings Despite the characteristics of the community remained substantially unchanged during the period 2002–2009, carriage of quinolone-resistant E. coli was found to be common in 2009 both in humans (45% nalidixic acid, 14% ciprofloxacin) and animals (54% nalidixic acid, 23% ciprofloxacin). Ciprofloxacin-resistant isolates of human and animal origin showed multidrug resistance phenotypes, a high level of genetic heterogeneity, and a combination of GyrA (Ser83Leu and Asp87Asn) and ParC (Ser80Ile) substitutions commonly observed in fluoroquinolone-resistant clinical isolates of E. coli. Conclusions Remoteness and absence of antibiotic selective pressure did not protect the community from the remarkable emergence of quinolone resistance in E. coli. Introduction of the resistant strains from antibiotic-exposed settings is the most likely source, while persistence and dissemination in the absence of quinolone exposure is likely mostly related with poor sanitation. Interventions aimed at reducing the spreading of resistant isolates (by improving sanitation and water/food safety) are urgently needed to preserve the efficacy of quinolones in resource-limited countries, as control strategies based only on antibiotic restriction policies are unlikely to succeed in those settings.
Riccobono, Eleonora; Fernandez, Connie; Mantella, Antonia; Magnelli, Donata; Mannini, Dario; Strohmeyer, Marianne; Bartalesi, Filippo; Rodriguez, Hugo; Gotuzzo, Eduardo; Rossolini, Gian Maria
Agar dilution MIC determination was used to compare the activity of DK-507k with those of ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, sitafloxacin, amoxicillin, cefuroxime, erythromycin, azithromycin, and clarithromycin against 113 penicillin-susceptible, 81 penicillin-intermediate, and 67 penicillin-resistant pneu- mococci (all quinolone susceptible). DK-507k and sitafloxacin had the lowest MICs of all quinolones against quinolone-susceptible strains (MIC at which 50% of isolates were inhibited
Frederick A. Browne; Bulent Bozdogan; Catherine Clark; Linda M. Kelly; Lois Ednie; Klaudia Kosowska; Bonifacio Dewasse; Michael R. Jacobs; Peter C. Appelbaum
In the past 20 years, an increased discrepancy between new available antibacterials and the emergence of multidrug-resistant strains has been observed. This condition concerns physicians involved in the treatment of central nervous system (CNS) infections, for which clinical and microbiological success depends on the rapid achievement of bactericidal concentrations. In order to accomplish this aim, the choice of drugs is based on their disposition toward the cerebrospinal fluid (CSF), which is influenced by the physicochemical characteristics of antibacterials. A reduced distribution into CSF has been documented for beta-lactams, especially cephalosporins and carbapenems, on the basis of their hydrophilic nature. However, they represent a cornerstone of the majority of combined therapeutic schemes for their ability to achieve bactericidal concentrations, especially in the presence of inflamed meninges. The good tolerability of beta-lactams makes possible high daily dose intensities, which may be associated with increased probability of cure. Furthermore, the adoption of continuous infusion seems to be a fruitful option. Fluoroquinolones, namely moxifloxacin, and antituberculosis drugs, together with the agents such as linezolid, reach the highest CSF/plasma concentration ratio, which is greater than 0.8, and for most of these drugs it is near 1. For all drugs that are currently used for the treatment of CNS infections, the evaluation of pharmacokinetic/pharmacodynamic parameters, on the basis of dosing regimens and their time-dependent or concentration-dependent pattern of bacterial killing, remains an important aspect of clinical investigation and medical practice. PMID:23605634
Di Paolo, Antonello; Gori, Giovanni; Tascini, Carlo; Danesi, Romano; Del Tacca, Mario
Novel drug delivery systems such as nanoparticles (NPs) have been proved to enhance the effectiveness of many drugs. Clarithromycin is a broad spectrum macrolide antibiotic, used in many infectious conditions like upper and lower respiratory tract infections, and skin and other soft tissue infections. This paper describes the preparation and enhanced in vitro antibacterial activities of clarithromycin loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles. A modified quasi-emulsion solvent diffusion (MQESD) method was used to prepare clarithromycin (CLR) NPs. The antibacterial activity of the NPs was evaluated using the agar well diffusion method against Escherichia coli (PTCC 1330), Haemophilus influenzae (PTCC 1623), Salmonella typhi (PTCC 1609), Staphylococcus aureus (PTCC 1112) and Streptococcus pneumoniae (PTCC 1240). The inhibition zone diameters related to each nano formulation were compared with those for untreated CLR at the same concentrations. The results indicated that the mean inhibition zone diameters of NPs against all the bacteria tested were significantly higher than those of untreated CLR, particularly in the case of S. aureus. The increased potency of CLR NPs may be related to some physicochemical properties of NPs like modified surface characteristics, lower drug degradation, and increased drug adsorption and uptake. PMID:22393833
Valizadeh, H; Mohammadi, G; Ehyaei, R; Milani, M; Azhdarzadeh, M; Zakeri-Milani, P; Lotfipour, F
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The pharmacokinetics of CP-74,667 (7-(8'-methyl-3',8'-diazabicyclo[3.2.1]oct-3'-yl)-1-cyclopropyl-6- fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid) were studied following oral or parenteral administration in mice, rats, rabbits, dogs, and cynomolgus monkeys. The mean peak levels of CP-74,667 in serum following a single oral dose of 20 mg/kg of body weight were similar in all species, with a range of 3.7 micrograms/ml in mice to 5.6 micrograms/ml in dogs. In contrast, elimination half-lives were species dependent, with mean values of 2.1, 1.8, 4.5, 7.8, and 13.1 h in mice, rats, rabbits, dogs, and monkeys, respectively. The oral bioavailability of CP-74,667 was 100% in dogs and monkeys, as determined by intravenous-oral crossover experiments. The maximum concentration of drug in serum and area under the concentration-time curve (AUC) of CP-74,667 in dogs were proportional to dose over the range of 5 to 40 mg/kg. Accumulation of drug in serum was observed following the administration of four once-a-day doses of 7.1 mg/kg in monkeys (mimicking a 500-mg human dose), with significant increases in half-life, maximum and minimum concentrations of drug in serum, and AUC. The good tissue penetration of CP-74,667 suggested by a volume of distribution in excess of 2 liters/kg in dogs and monkeys was confirmed by tissue distribution studies with the same species, which demonstrated tissue concentrations (except for those in brain tissue) greater than 1.45 times higher than corresponding levels in serum. The mean urinary recoveries of unchanged drug were 17.7% in rats, 7.8% in monkeys, and 4.9% in dogs. Metabolism studies in dogs, following intravenous dosing, indicated that renal excretion of CP-74,667-related materials accounted for 41.6% of the administered dose, while biliary recoveries accounted for 6.8%. The CP-74,667 N-oxide metabolite was the primary drug-related material eliminated via renal excretion (37.2% of dose). The pharmacokinetics of CP-74,667 describe a quinolone with complete oral absorption, linear pharmacokinetics, a long elimination half-life, and wide distribution into tissues.
Girard, D; Gootz, T D; McGuirk, P R
This article highlights current trends and advances in exploiting natural sources for the deployment of novel and potent anti-infective countermeasures. The key challenge is to therapeutically target bacterial pathogens that exhibit a variety of puzzling and evolutionarily complex resistance mechanisms. Special emphasis is given to the strengths, weaknesses, and opportunities in the natural product antibacterial drug discovery arena, and to emerging applications driven by advances in bioinformatics, chemical biology, and synthetic biology in concert with exploiting bacterial phenotypes. These efforts have identified a critical mass of natural product antibacterial lead compounds and discovery technologies with high probability of successful implementation against emerging bacterial pathogens. PMID:23890825
Bologa, Cristian G; Ursu, Oleg; Oprea, Tudor I; Melançon, Charles E; Tegos, George P
The emergence of resistance to antibacterial agents is a pressing concern for human health. New drugs to combat this problem are therefore in great demand, but as past experience indicates, the time for resistance to new drugs to develop is often short. Conventionally, antibacterial drugs have been developed on the basis of their ability to inhibit bacterial multiplication, and this
Yanmin Hu; Richard Bax; Clive Page; Anthony Coates
3-Substituted 2-quinolones are obtained via a novel, metal-free transannulation reaction of 2-substituted indoles with 2-nitroalkenes in polyphosphoric acid. The reaction can be used in conjunction with the Fisher indole synthesis offering a practical three-component heteroannulation methodology to produce 2-quinolones from arylhydrazines, 2-nitroalkenes and acetophenone. PMID:23999797
Aksenov, Alexander V; Smirnov, Alexander N; Aksenov, Nicolai A; Aksenova, Inna V; Frolova, Liliya V; Kornienko, Alexander; Magedov, Igor V; Rubin, Michael
Polygodial was found to possess moderate antibacterial activity against gram-positive bacteria including Bacillus subtilis, Staphylococcus aureus and gram-negative bacteria including Escherichia coli and Salmonella choleraesuis with minimum bactericidal concentrations (MBC) of 100 and 100 microg/mL (0.34 mm) and 100 and 50 microg/mL, respectively. The time kill curve study showed that polygodial was bactericidal against B. subtilis and S. choleraesuis. However, there was a difference in its bactericidal action against endospore-forming B. subtilis and food-borne S. choleraesuis. PMID:16372365
Kubo, Isao; Fujita, Ken-ichi; Lee, Sang Hwa; Ha, Tae Joung
In order to achieve high local bioactivity and low systemic side effects of antibiotics in the treatment of dental, periodontal and bone infections, a localized and temporally controlled delivery system is crucial. In this study, a three-dimensional (3D) porous tissue engineering scaffold was developed with the ability to release antibiotics in a controlled fashion for long-term inhibition of bacterial growth. The highly soluble antibiotic drug, Doxycycline (DOXY), was successfully incorporated into PLGA nanospheres using a modified water-in-oil-in-oil (w/o/o) emulsion method. The PLGA nanospheres (NS) were then incorporated into prefabricated nanofibrous PLLA scaffolds with a well interconnected macroporous structure. The release kinetics of DOXY from four different PLGA NS formulations on a PLLA scaffold was investigated. DOXY could be released from the NS-scaffolds in a locally and temporally controlled manner. The DOXY release is controlled by DOXY diffusion out of the NS and is strongly dependent upon the physical and chemical properties of the PLGA. While PLGA50-6.5K, PLGA50-64K, and PLGA75-113K NS-scaffolds discharge DOXY rapidly with a high initial burst release, PLGA85-142K NS-scaffold can extend the release of DOXY to longer than 6 weeks with a low initial burst release. Compared to NS alone, the NS incorporated on a 3-D scaffold had significantly reduced the initial burst release. In vitro antibacterial tests of PLGA85 NS-scaffold demonstrated its ability to inhibit common bacterial growth (S.aureus and E.coli) for a prolonged duration. The successful incorporation of DOXY onto 3-D scaffolds and its controlled release from scaffolds extends the usage of nano-fibrous scaffolds from the delivery of large molecules such as growth factors to the delivery of small hydrophilic drugs, allowing for a broader application and a more complex tissue engineering strategy.
Feng, Kai; Sun, Hongli; Bradley, Mark A.; Dupler, Ellen J.; Giannobile, William V.; Ma, Peter X.
Toxoplasma gondii is a widely distributed protozoan pathogen that causes devastating ocular and central nervous system disease. We show that the endochin-like quinolone (ELQ) class of compounds contains extremely potent inhibitors of T. gondii growth in vitro and is effective against acute and latent toxoplasmosis in mice. We screened 50 ELQs against T. gondii and selected two lead compounds, ELQ-271 and ELQ-316, for evaluation. ELQ-271 and ELQ-316, have in vitro IC(50) values of 0.1 nM and 0.007 nM, respectively. ELQ-271 and ELQ-316 have ED(50) values of 0.14 mg/kg and 0.08 mg/kg when administered orally to mice with acute toxoplasmosis. Moreover, ELQ-271 and ELQ-316 are highly active against the cyst form of T. gondii in mice at low doses, reducing cyst burden by 76-88% after 16 d of treatment. To investigate the ELQ mechanism of action against T. gondii, we demonstrate that endochin and ELQ-271 inhibit cytochrome c reduction by the T. gondii cytochrome bc(1) complex at 8 nM and 31 nM, respectively. We also show that ELQ-271 inhibits the Saccharomyces cerevisiae cytochrome bc(1) complex, and an M221Q amino acid substitution in the Q(i) site of the protein leads to >100-fold resistance. We conclude that ELQ-271 and ELQ-316 are orally bioavailable drugs that are effective against acute and latent toxoplasmosis, likely acting as inhibitors of the Q(i) site of the T. gondii cytochrome bc(1) complex. PMID:23019377
Doggett, J Stone; Nilsen, Aaron; Forquer, Isaac; Wegmann, Keith W; Jones-Brando, Lorraine; Yolken, Robert H; Bordón, Claudia; Charman, Susan A; Katneni, Kasiram; Schultz, Tracey; Burrows, Jeremy N; Hinrichs, David J; Meunier, Brigitte; Carruthers, Vern B; Riscoe, Michael K
A series of novel derivatives of 4H-pyrido[1,2-a]pyrimidine, 1,4-dihydro-4-oxo-1,5-naphthyridine and 1,4-dihydro-4-oxo-1,6-naphthyridine were prepared and their biological\\u000a activity was compared with that of nalidixic acid. Thein vitro antibacterial activity of the tested compounds was lower than that of nalidixic acid except for two agents,1b and2c, with a higher activity againstEnterococcus faecalis. The compounds were tested for their ability to cure four plasmids
A. Belicová; M. Seman; V. Milata; D. Ilavský; L. Ebringer
Nontyphoidal Salmonella enterica strains with a nonclassical quinolone resistance phenotype were isolated from patients returning from Thailand or Malaysia to Finland. A total of 10 isolates of seven serovars were studied in detail, all of which had reduced susceptibility (MIC ? 0.125 ?g/ml) to ciprofloxacin but were either susceptible or showed only low-level resistance (MIC ? 32 ?g/ml) to nalidixic acid. Phenotypic characterization included susceptibility testing by the agar dilution method and investigation of efflux activity. Genotypic characterization included the screening of mutations in the quinolone resistance-determining regions (QRDR) of gyrA, gyrB, parC, and parE by PCR and denaturing high-pressure liquid chromatography and the amplification of plasmid-mediated quinolone resistance (PMQR) genes qnrA, qnrB, qnrS, qnrD, aac(6?)-Ib-cr, and qepA by PCR. PMQR was confirmed by plasmid analysis, Southern hybridization, and plasmid transfer. No mutations in the QRDRs of gyrA, gyrB, parC, or parE were detected with the exception of a Thr57-Ser substitution within ParC seen in all but the S. enterica serovar Typhimurium strains. The qnrA and qnrS genes were the only PMQR determinants detected. Plasmids carrying qnr alleles were transferable in vitro, and the resistance phenotype was reproducible in Escherichia coli DH5? transformants. These data demonstrate the emergence of a highly mobile qnr genotype that, in the absence of mutation within topoisomerase genes, confers the nontypical quinolone resistance phenotype in S. enterica isolates. The qnr resistance mechanism enables bacteria to survive elevated quinolone concentrations, and therefore, strains carrying qnr alleles may be able to expand during fluoroquinolone treatment. This is of concern since nonclassical quinolone resistance is plasmid mediated and therefore mobilizable.
Gunell, Marianne; Webber, Mark A.; Kotilainen, Pirkko; Lilly, Andrew J.; Caddick, Jonathan M.; Jalava, Jari; Huovinen, Pentti; Siitonen, Anja; Hakanen, Antti J.; Piddock, Laura J. V.
Nontyphoidal Salmonella enterica strains with a nonclassical quinolone resistance phenotype were isolated from patients returning from Thailand or Malaysia to Finland. A total of 10 isolates of seven serovars were studied in detail, all of which had reduced susceptibility (MIC > or = 0.125 microg/ml) to ciprofloxacin but were either susceptible or showed only low-level resistance (MIC < or = 32 microg/ml) to nalidixic acid. Phenotypic characterization included susceptibility testing by the agar dilution method and investigation of efflux activity. Genotypic characterization included the screening of mutations in the quinolone resistance-determining regions (QRDR) of gyrA, gyrB, parC, and parE by PCR and denaturing high-pressure liquid chromatography and the amplification of plasmid-mediated quinolone resistance (PMQR) genes qnrA, qnrB, qnrS, qnrD, aac(6')-Ib-cr, and qepA by PCR. PMQR was confirmed by plasmid analysis, Southern hybridization, and plasmid transfer. No mutations in the QRDRs of gyrA, gyrB, parC, or parE were detected with the exception of a Thr57-Ser substitution within ParC seen in all but the S. enterica serovar Typhimurium strains. The qnrA and qnrS genes were the only PMQR determinants detected. Plasmids carrying qnr alleles were transferable in vitro, and the resistance phenotype was reproducible in Escherichia coli DH5alpha transformants. These data demonstrate the emergence of a highly mobile qnr genotype that, in the absence of mutation within topoisomerase genes, confers the nontypical quinolone resistance phenotype in S. enterica isolates. The qnr resistance mechanism enables bacteria to survive elevated quinolone concentrations, and therefore, strains carrying qnr alleles may be able to expand during fluoroquinolone treatment. This is of concern since nonclassical quinolone resistance is plasmid mediated and therefore mobilizable. PMID:19596880
Gunell, Marianne; Webber, Mark A; Kotilainen, Pirkko; Lilly, Andrew J; Caddick, Jonathan M; Jalava, Jari; Huovinen, Pentti; Siitonen, Anja; Hakanen, Antti J; Piddock, Laura J V
The relative efficacy, safety and ecological implications of macrolides vs. quinolones in the treatment of community-acquired pneumonia (CAP) are debatable. We performed a systematic review and meta-analysis of randomized controlled trials comparing any macrolide vs. any quinolone for the treatment of CAP among adult inpatients or outpatients, as monotherapy or both in combination with a beta-lactam. We did not limit inclusion by pneumonia severity, publication status, language or date of publication. The primary outcomes assessed were 30-day all-cause mortality and treatment failure. Two authors independently extracted the data. Fixed effect meta-analysis of risk ratios (RRs) with 95% confidence intervals was performed. Sixteen trials (4989 patients) fulfilling inclusion criteria were identified, mostly assessing outpatients with mild to moderate CAP. All-cause mortality was not significantly different for macrolides vs. quinolones, RR 1.03 (0.63-1.68, seven trials), with a low event rate (2%). Treatment failure was significantly lower with quinolones, RR 0.78 (0.67-0.91, 16 trials). The definition of failure used in the primary studies was not clearly representative of patients' benefit. Microbiological failure was lower with quinolones, RR 0.63 (0.49-0.81, 13 trials). All adverse events, adverse events requiring discontinuation and any premature antibiotic discontinuation were significantly more frequent with macrolides, mainly on account of gastrointestinal adverse events. Resistance development was not assessed in the trials. Randomized controlled trials show an advantage of quinolones in the treatment of CAP with regard to clinical cure without need for antibiotic modification at end of treatment and gastrointestinal adverse events. The clinical significance of this advantage is unclear. PMID:22489673
Skalsky, K; Yahav, D; Lador, A; Eliakim-Raz, N; Leibovici, L; Paul, M
We have studied by PCR and DNA sequencing the presence of the qnrA, qnrB, qnrS, aac(6?)-Ib-cr, qepA, intI1, and ISCR1 genes in 200 clinical isolates of Enterobacter cloacae (n = 153) and E. aerogenes (n = 47) consecutively collected between January 2004 and October 2005 in two hospitals located in Santander (northern Spain) and Seville (southern Spain). Mutations in the quinolone resistance-determining region of gyrA and parC also were investigated in organisms containing plasmid-mediated quinolone resistance genes. The isolates had different resistant phenotypes, including AmpC hyperproduction, extended-spectrum ?-lactamase production, resistance or decreased susceptibility to quinolones, and/or resistance to aminoglycosides. Among the 116 E. cloacae isolates from Santander, qnrS1, qnrB5, qnrB2, and aac(6?)-Ib-cr were detected in 22 (19%), 1 (0.9%), 1 (0.9%), and 3 (2.6%) isolates, respectively. Twenty-one, 17, and 2 qnrS1-positive isolates also contained blaLAP-1, intI1, and ISCR1, respectively. A qnrB7-like gene was detected in one E. aerogenes isolate from Santander. No plasmid-mediated quinolone resistance gene was detected in the isolates from Seville. The qnrS1-containing isolates corresponded to four pulsed-field gel electrophoresis patterns and showed various levels of resistance to quinolones. Six isolates were susceptible to nalidixic acid and presented reduced susceptibility to ciprofloxacin. The qnrS1 gene was contained in a conjugative plasmid of ca. 110 kb, and when the plasmid was transferred to recipient strains that did not have a specific mechanism of quinolone resistance, the ciprofloxacin MICs ranged from 0.047 to 0.125 ?g/ml.
Cano, M. E.; Rodriguez-Martinez, J. M.; Aguero, J.; Pascual, A.; Calvo, J.; Garcia-Lobo, J. M.; Velasco, C.; Francia, M. V.; Martinez-Martinez, L.
Sertralin is a psychotropic drug which acts by inhibiting the selective serotonin re-uptake in the synaptic area. Previous studies have shown that some antidepressant agents have antibacterial activity. The aim of this study was to investigate the in vitro antibacterial activity of sertralin. A total of 224 bacterial strains isolated from clinical specimens together with standard control strains were included to the study. The antibacterial activity of sertralin was determined by microdilution method in Mueller-Hinton broth according to the Clinical and Laboratory Standards Institute (CLSI) guideline. The minimum inhibitory concentration (MIC) values were found to be 4-32 microg/ml for 22 methicillin-susceptible Staphylococcus aureus strains, 16-32 microg/ml for 25 methicillin-resistant S. aureus strains, 8-32 microg/ml for 20 methicillin-resistant coagulase-negative staphylococci strains, 16-32 microg/ml for 4 vancomycin-susceptible Enterococcus faecalis strains, 0.5-32 microg/ml for 10 vancomycin-susceptible Enterococcus faecium strains, 2-8 microg/ml for 12 vancomycin-resistant E. faecium strains, 16-128 microg/ml for 21 Acinetobacter baumannii strains, 4->128 microg/ml for 20 Klebsiella pneumoniae strains, 0.25-128 microg/ml for 24 Escherichia coil strains, 64->128 microg/ml for 22 Pseudomonas aeruginosa strains, 128->128 microg/ml for 2 Proteus vulgaris strains, 64->128 microg/ml for 8 Proteus mirabilis strains, 32->128 microg/ml for 7 Stenotrophomonas maltophilia strains, 32-128 microg/ml for 21 Enterobacter cloacae strains and 8-128 microg/ml for 6 Enterobacter aerogenes strains. The MIC values of sertralin against standard strains were as follows; 16 microg/ml for S. aureus ATCC 29213 (methicillin-susceptible), 32 microg/ml for S. aureus ATCC 43300 (methicillin-resistant), 16 microg/ml for E. faecalis ATCC 29212, 32 microg/ml for K. pneumoniae ATCC 700603, 32 microg/ml for E. coli ATCC 25922 and > 128 microg/ml for P. aeruginosa ATCC 27853. Sertralin has showed antibacterial activity mainly against gram-positive bacteria, and it was surprising that MIC values of vancomycin-resistant enterococci were lower than those of vancomycin-susceptible ones. Further in vivo and in vitro studies are required to provide reliable data about the use of sertralin as an adjuvant agent in the antibacterial treatment of infections caused by multidrug-resistant bacteria. PMID:20084919
Coban, Ahmet Yilmaz; Tanriverdi Cayci, Yeliz; Kele? Uluda?, Selma; Durupinar, Belma
Acute pyelonephritis is a potentially organ-damaging and life-threatening infection. A 37-year old woman was admitted to Intensive Care Unit in septic shock and multi-organ failure due to acute pyelonephritis with systemic bacterial dissemination caused by a quinolone-resistant Escherichia coli. The patient, a previously healthy woman, reported recurrent episodes of urinary tract infection in the previous 3 years, which were treated with quinolones. Treatment course with broad-spectrum antimicrobial agents reversed her septic shock and multi-organ failure. However, pyelonephritis progressed to intrarenal and perirenal abscesses formation. The patient fully recovered after surgical removal of the infected kidney. PMID:23935324
Katsiari, M; Nikolaou, C; Roussou, Z; Triantopoulou, C; Apessou, D; Platsouka, Ed; Maguina, A
The antibacterial activities of tosufloxacin and other quinolones against and apparent uptakes of tosufloxacin and other quinolones by outer membrane mutants of Escherichia coli, Proteus mirabilis, and Salmonella typhimurium were studied. The hydrophobicity of tosufloxacin was nearly equal to that of ofloxacin or lower than those of sparfloxacin and nalidixic acid. OmpF- and OmpC-deficient E. coli and 40-kDa porin-deficient P. mirabilis mutants were twofold more susceptible to tosufloxacin and sparfloxacin but two- to fourfold less susceptible to other quinolones than their parent strains. In S. typhimurium lipopolysaccharide-deficient (rough) mutants, the differences in susceptibility to tosufloxacin were similar to those to sparfloxacin and nalidixic acid. The apparent uptake of tosufloxacin by intact cells was increased in porin-deficient mutants compared with that by their parent strain. These results suggest that the permeation route of tosufloxacin across the outer membrane is different from that of other fluoroquinolones and that tosufloxacin may permeate mainly through the nonporin pathway, presumably phospholipid bilayers. However, this characteristic is independent of the hydrophobicity of the molecule. Images
Mitsuyama, J; Itoh, Y; Takahata, M; Okamoto, S; Yasuda, T
The development of a State-based confirmatory testing capability for antibiotic residues in meat in Australia has allowed the rapid feedback to producers failing to comply with antibiotic maximum residue limits. The identification of problem areas in various categories of livestock, and subsequent focused surveillance programs, has reduced the prevalence of antibacterial residues in both domestic and export meat products. Failure to observe withholding periods of antibacterial drugs after treatment is the most significant cause of non-compliance. In the period July 1991 to June 1993 the compliance rate for antibacterial residues for all species was 99.9%. PMID:7702475
Nicholls, T J; Blackman, N L; Stephens, I B; Wild, R J
We cloned a gene, ECL_03329, from the chromosome of Enterobacter cloacae ATCC13047, using a drug-hypersensitive Escherichia coli KAM32 cell as the host. We show here that this gene, designated emmdR, is responsible for multidrug resistance in E. cloacae. E. coli KAM32 host cells containing the cloned emmdR gene (KAM32/pEMMDR28) showed decreased susceptibilities to benzalkonium chloride, norfloxacin, ciprofloxacin, levofloxacin, ethidium bromide, acriflavine, rhodamine6G, and trimethoprim. emmdR-deficient E. cloacae cells (Ec?emmdR) showed increased susceptibilities to several of the antimicrobial agents tested. EmmdR has twelve predicted transmembrane segments and some shared identity with members of the Multidrug and Toxic Compound Extrusion (MATE) family of transporters. Study of the antimicrobial agent efflux activities revealed that EmmdR is an H+-drug antiporter but not a Na+ driven efflux pump. These results indicate that EmmdR is responsible for multidrug resistance and pumps out quinolones from E. cloacae.
He, Gui-Xin; Thorpe, Conner; Wash, Dennis; Crow, Robert; Chen, Hui-Zhong; Kumar, Sanath; Varela, Manuel F.
The objective of the present research was to formulate poly(lactide-co-glycolide) nanoparticles loaded with azithromycin with appropriate physicochemical properties and antimicrobial activity. Azithromycin-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) were prepared in three different ratios of drug to polymer by nanoprecipitation technique. Antibacterial activity of these nanoparticles was examined against gram-negative intra cellular microorganism Salmonella typhi. The antibacterial effect was investigated using serial
Ghobad Mohammadi; Hadi Valizadeh; Mohammad Barzegar-Jalali; Farzaneh Lotfipour; Khosro Adibkia; Morteza Milani; Morteza Azhdarzadeh; Farhad Kiafar; Ali Nokhodchi
We prepared four differently shaped Te nanomaterials (NMs) as antibacterial reagents against Escherichia coli. By controlling the concentrations of hydrazine (N(2)H(4)) as reducing agent, NaCl, and temperature, we prepared Te nanowires, nanopencils, nanorices, and nanocubes. These four Te NMs resulted in a live/dead ratio of E. coli cells of less than 0.1, which is smaller than that of Ag nanoparticles. The order of antibacterial activity against E. coli is nanocubes ? nanorices > nanopencils ? nanowires. This is in good agreement with the concentration order of tellurite (TeO(3)(2-)) ions released from Te NMs in E. coli cells, revealing that TeO(3)(2-) ions account for the antibacterial activity of the four Te NMs. We found that spherical Te nanoparticles (32 nm in diameter) with TeO(3)(2-) ions were formed in the E. coli cells. Compared to Ag nanoparticles that are commonly used as antibacterial reagents, Te NMs have higher antibacterial activity and lower toxicity. Thus, Te NMs hold great practical potential as a new and efficient antibacterial agent. PMID:22438287
Lin, Zong-Hong; Lee, Chia-Hsin; Chang, Hsin-Yun; Chang, Huan-Tsung
We determined the MICs of 63 quinolones against 14 selected reference and clinical strains of the Mycobacterium avium-Mycobacterium intracellulare complex. Sixty-one of the compounds were selected from the quinolone library at Parke-Davis, Ann Arbor, Mich., including N-1-tert-butyl-substituted agents. T 3761 and tosufloxacin were also tested. The activities of all 63 compounds were compared with those of ciprofloxacin and sparfloxacin. The results showed 45 of the quinolones to be active against the M. avium-M. intracellulare complex, with MICs at which 50% of the strains were inhibited (MIC50s) of less than 32 micrograms/ml. Twenty-four of these quinolones had activities equivalent to or greater than that of ciprofloxacin, and nine of them had activities equivalent to or greater than that of sparfloxacin. The most active compounds were the N-1-tert-butyl-substituted quinolones, PD 161315 and PD 161314, with MIC50s of 0.25 microgram/ml and MIC90s of 1 microgram/ml; comparable values for ciprofloxacin were 2 and 4 micrograms/ml, respectively, while for sparfloxacin they were 1 and 2 micrograms/ml, respectively. The next most active compounds, with MIC50s of 0.5 microgram/ml and MIC90s of 1 microgram/ml, were the N-1-cyclopropyl-substituted quinolones, PD 138926 and PD 158804. These values show that the tert-butyl substituent is at least as good as cyclopropyl in rendering high levels of antimycobacterial activity. However, none of the quinolones showed activity against ciprofloxacin-resistant laboratory-derived M. avium-M. intracellulare complex strains. A MULTICASE program-based structure-activity relationship analysis of the inhibitory activities of these 63 quinolones and 109 quinolones previously studied against the most resistant clinical strain of M. avium was also performed and led to the identification of two major biophores and two biophobes.
Klopman, G; Fercu, D; Renau, T E; Jacobs, M R
The newer quinolones, ciprofloxacin, enoxacin, fleroxacin, lomefloxacin, norfloxacin, ofloxacin and pefloxacin are highly effective antimicrobial agents against the majority of bacteria responsible for urinary tract infections and bacterial prostatitis. The pharmacokinetic properties of these agents after oral administration result in high concentrations in human urine, as well as in prostatic fluid and prostatic tissue. Ciprofloxacin, enoxacin and lomefloxacin produce the
V. T. Andriole
Laribacter hongkongensis is a food-borne bacterium associated with community-acquired gastroenteritis and diarrhoea. Quinolone resistance was recently reported in bacterial isolates from aquatic products, but the molecular mechanisms for resistance were still unknown. In this study, a total of 157 L. hongkongensis strains were isolated from grass carps (n?=?443) and Chinese tiger frogs (n?=?171). Twenty-one ciprofloxacin-resistant strains were analysed for mutations in quinolone resistance-determining regions (QRDR), acquired quinolone resistance (AQR) genes and the role of efflux pumps in resistance. All QRDR mutations in gyrA (codons 85 and 89) and parC (codons 83 and 231) were found to be closely associated with ciprofloxacin resistance. The AQR gene aac(6')-Ib-cr was found in 42.9?% (9/21) of the resistant strains, but qnrA, qnrB, qnrC, qnrD, qnrS and qepA were not detected. No significant change of MICs to ciprofloxacin was observed in the presence of an efflux pump inhibitor, indicating the role of efflux pump was probably absent. All 21 ciprofloxacin-resistant strains showed different electrophoretic patterns, which suggested they were not genetically related. These data highlight the importance of QRDR mutations and the AQR gene aac(6')-Ib-cr during the development of quinolone resistance in a heterogeneous population of L. hongkongensis. PMID:23906590
Chen, Ding-Qiang; Yang, Ling; Luo, Yu-Ting; Mao, Min-Jie; Lin, Yong-Ping; Wu, Ai-Wu
Antimicrobial susceptibility was determined in 15 epidemiologically unrelated clinical isolates of Acinetobacter genospecies 3. Moreover, the mechanisms of resistance to some ?-lactam antibiotics may be associated with the presence of a chromosomal cephalosporinase, AmpC, and the resistance to quinolones related to mutations in the gyrA and parC genes.
Ribera, A.; Fernandez-Cuenca, F.; Beceiro, A.; Bou, G.; Martinez-Martinez, L.; Pascual, A.; Cisneros, J. M.; Rodriguez-Bano, J.; Pachon, J.; Vila, J.
Antibiotic residues that may be present in carcasses of medicated livestock could pass to and greatly reduce scavenger wildlife populations. We surveyed residues of the quinolones enrofloxacin and its metabolite ciprofloxacin and other antibiotics (amoxicillin and oxytetracycline) in nestling griffon Gyps fulvus, cinereous Aegypius monachus and Egyptian Neophron percnopterus vultures in central Spain. We found high concentrations of antibiotics in
Jesús Á. Lemus; Guillermo Blanco; Javier Grande; Bernardo Arroyo; Marino García-Montijano; Felíx Martínez; Dee Carter
Quinolone antibiotics (QNs) including norfloxacin (NOR), enrofolxacin (ENR), ciprofloxacin (CIP) and lomefloxacin (LOM) in vegetable samples collected from Guangzhou were determined by high performance liquid chromatography (HPLC) coupled with fluorescent detector (FLD). The detected frequency of QNs was 96% in vegetables. The total concentration of quinolones (sigma QNs) detected in vegetable ranged from 1.0 microg/kg to 1 683.1 microg/kg (F.W.). Leafy vegetable topped the content of quinolones among the three types of vegetables, followed by the melon-fruit vegetable and rhizome vegetable. The detected frequency of the four quinolone antibiotics ranked as NOR > CIP > LOM > ENR. Except ENR, concentrations of CIP, NOR, LOM and sigma QNs in pollution-free vegetable, green vegetable and organic vegetable were higher than those in routine cultivated vegetables. The maximum contribution to ADI value (caculated by the sum of CIP and ENR) is estimated up to 41.5% and 83% for adults and children respectively via consumption of vegetables. PMID:21229759
Li, Yan-Wen; Zhang, Yan; Mo, Ce-Hui; Tai, Yi-Ping; Wu, Xiao-Lian; Wang, Ji-Yang; Su, Qing-Yun
We used the multilocus sequence typing (MLST) method to evaluate the genetic diversity of 46 Campylobacter jejuni isolates from chickens and to determine the link between quinolone resistance and sequence type (ST). There were a total of 16 ST genotypes, and the majority of them belonged to seven clonal complexes previously identified by using isolates from human disease. The ST-353 complex was the most common complex, whereas the ST-21, ST-42, ST-52, and ST-257 complexes were less well represented. The resistance phenotype varied for each ST, and the Thr-86-Ile substitution in the GyrA protein was the predominant mechanism of resistance to quinolone. Nine of the 14 isolates having the Thr-86-Ile substitution belonged to the ST-353 complex. MLST showed that the emergence of quinolone resistance is not related to the diffusion of a unique clone and that there is no link between ST genotype and quinolone resistance. Based on silent mutations, different variants of the gyrA gene were shown to exist for the same ST. These data provide useful information for understanding the epidemiology of C. jejuni in Senegal.
Kinana, Alfred Dieudonne; Cardinale, Eric; Tall, Fatou; Bahsoun, Ibrahim; Sire, Jean-Marie; Garin, Benoit; Breurec, Sebastien; Boye, Cheikh Saad-Bouh; Perrier-Gros-Claude, Jean-David
Bacillus anthracis is a potential biological warfare agent. Its ability to develop resistance to antimicrobial agents currently recommended for the treatment of anthrax infection is a major concern. B. anthracis Sterne was grown from a live veterinary vaccine and used it to test for the development of resistance after 21 sequential subcultures in sub-inhibitory concentrations of doxycycline and three quinolones
Itzhak Brook; Thomas B Elliott; Howard I Pryor; Tamar E Sautter; Bryan T Gnade; Jayendrakumar H Thakar; Gregory B Knudson
Resistant variants of three clinical Pseudomonas aeruginosa isolates were obtained in the presence of aztreonam. The variants exhibited a four- to eightfold increase in the minimal inhibitory concentrations to ?-lactam antibiotics (except imipenem) to quinolones, such as norfloxacin and fleroxacin, chloramphenicol and tetracycline, but not to gentamicin and polymyxin B. ?-Lactamase production was barely detectable in both wild-type strains and
H. J. Leying; K. H. Büscher; W. Cullmann; R. L. Then
An improved microbiological screening assay is reported for the detection of quinolone residues in poultry muscle and eggs. The method was validated using fortified tissue samples and is the first microbial assay to effectively detect enrofloxacin, difloxacin, danofloxacin, as well as flumequine and oxolinic acid, at or below their EU maximum residue limits (MRL). The accuracy of the assay was
M. G. Pikkemaat; P. P. J. Mulder; J. W. A. Elferink; A. De Cocq; M. W. F. Nielen; H. J. Van Egmond
We determined the prevalence of, and risk factors for, fecal quinolone-resistant Escherichia coli (QREC) in 324 children from Yucatan, Mexico. QREC was higher in children with recent Salmonella infection (100%) than in children with diarrhea (61%) or healthy children (54%), (p= 0.007). Multivariate...
BACKGROUND AND OBJECTIVES: Gonococcal fluoroquinolone resistance is now a significant problem in Japan. We generated gonococcal mutants resistant to norfloxacin in vitro from norfloxacin sensitive isolates and analysed the contribution of three known mechanisms of quinolone resistance in Neisseria gonorrhoeae. MATERIALS AND METHODS: Three clinical isolates of N gonorrhoeae susceptible to norfloxacin were exposed to increasing concentrations of norfloxacin. To
M. Tanaka; S. Sakuma; K. Takahashi; T. Nagahuzi; T. Saika; I. Kobayashi; J. Kumazawa
Drug discovery program is a complex scientific process, with very low successful rate of 1\\/5000 compounds, which might be further developed for therapeutic usage. To accelerate the drug discovery process, new “omics” technology has been used. We have described how to use proteomics technology of two-dimensioal gel to identify the protein target of an antibacterial compound. The digital images of
KuoYuan Hwa; Di-Shuan Chiang; Chen-Wen Yao
Aims To investigate the concern, raised by spontaneous reports received by the German regulatory authorities, that use of quinolone antibiotics may increase the risk for suicide and other suicidal behaviours. Methods We carried out a nested case-control study using the General Practice Research Database (GPRD). We compared the risk of suicidal behaviours among users of quinolones, other antibiotics and no antibiotics. Results From January 1, 1991 through April 30, 1995 we identified 348 cases of suicide, attempted suicide, or suicidal ideation and 808 controls. Compared with controls, cases who had received a prescription for a quinolone in the 30 days prior to the event had an adjusted relative risk (RR) estimate of 1.5 (95% CI 0.4–6.3) for any suicidal behaviour. Cases who had filled a prescription for a quinolone in the 31 to 180 days prior to their event had an adjusted RR estimate of 0.8 (95% CI 0.4–1.7) compared with controls. Cases who used other antibiotics in the 30 days prior to the event conferred an adjusted RR estimate of 1.1 (95% CI 0.6–2.2), and 0.9 (95% CI 0.6–1.3) for exposure in the 31 to 180 days prior to the event. The results were not materially different when suicide, suicide attempt, and suicidal ideation were analyzed separately. Conclusions We conclude that there is no material increased risk of suicidal behaviours for use of quinolone antibiotics compared with non-use or use of other antibiotics.
Jick, Susan S; Vasilakis, Catherine; Martinez, Carlos; Jick, Hershel
Within the past years, many researches on the synthesis, structure-activity relationships (SAR), antitumor, antiinflammatory and anti-bacterial activities of the pyrazole derivatives have been reported. Several pyrazole derivatives possess important pharmacological activities and they have been proved useful materials in drug research. Pyrazole derivatives play an important role in antitumor agents because of their good inhibitory activity against BRAF(V600E), EGFR, telomerase, ROS Receptor Tyrosine Kinase and Aurora-A kinase. In addition, pyrazole derivatives also show good antiinflammatory and anti-bacterial activities. In this review, the bioactivities of the pyrazole derivatives mentioned above will be summarized in detail. We sincerely hope that increasing knowledge of the SAR and cellular processes underlying the bioactivity of pyrazole derivatives will be beneficial to the rational design of new generation of small molecule drugs. PMID:23937232
Liu, Jia-Jia; Zhao, Meng-Yue; Zhang, Xin; Zhao, Xin; Zhu, Hai-Liang
Doxycycline is a tetracycline antibiotic with a potent antibacterial activity against a wide variety of bacteria. However, poor cellular penetration limits its use for the treatment of infectious disease caused by intracellular pathogens. One potential strategy to overcome this problem is the use of nanotechnology that can help to easily target the intracellular sites of infection. The antibacterial activity of these antibiotics is enhanced by encapsulating it in polymeric nanoparticles. In this study, we describe the improvement of the entrapment efficiency of doxycycline hydrochloride (doxycycline)-loaded PLGA:PCL nanoparticles up to 70% with variation of different formulation parameters such as polymer ratio, amount of drug loading (w/w), solvent selection, electrolyte addition, and pH alteration in the formulation. We have evaluated the efficacy of these nanoparticles over native doxycycline against a strain of Escherichia coli (DH5?) through growth inhibition and colony counting. The results indicate that doxycycline-loaded nanoparticles have superior effectiveness compared to native doxycycline against the above bacterial strain, resulting from the sustained release of doxycycline from nanoparticles. These results are encouraging for the use of these doxycycline-loaded nanoparticles for the treatment of infections caused by doxycycline-sensitive bacteria. PMID:22568901
Misra, Ranjita; Sahoo, Sanjeeb K
Liquid chromatography coupled to mass spectrometry nowadays plays an important role in the field of therapeutic drug monitoring\\u000a (TDM), especially of new compounds for which no immunoassays are available. This paper reviews LC–MS(–MS) methods published\\u000a recently for anti-infective drugs: antiretroviral drugs, other antiviral drugs, antibacterial drugs, antihelmintic drugs,\\u000a antimalarial drugs, and other antiprotozoal drugs. An overview of the different methods
Daniel M. Müller; Katharina M. Rentsch
As novel and drug-resistant bacterial strains continue to present an emerging health threat, the development of new antibacterial agents is critical. This includes making improvements to existing antibacterial scaffolds as well as identifying novel ones. The aim of this study is to apply a Bayesian classification QSAR approach to rapidly screen chemical libraries for compounds predicted to have antibacterial activity. Toward this end we assembled a data set of 317 known antibacterial compounds as well as a second data set of diverse, well-validated, non-antibacterial compounds from 215 PubChem Bioassays against various bacterial species. We constructed a Bayesian classification model using structural fingerprints and physicochemical property descriptors and achieved an accuracy of 84% and precision of 86% on an independent test set in identifying antibacterial compounds. To demonstrate the practical applicability of the model in virtual screening, we screened an independent data set of ~200k compounds. The results show that the model can screen top hits of PubChem Bioassay actives with accuracy up to ~76%, representing a 1.5-2-fold enrichment. The top screened hits represented a mixture of both known antibacterial scaffolds as well as novel scaffolds. Our study suggests that a well-validated Bayesian classification QSAR approach could compliment other screening approaches in identifying novel and promising hits. The data sets used in constructing and validating this model have been made publicly available. PMID:23013546
Singh, Narender; Chaudhury, Sidhartha; Liu, Ruifeng; AbdulHameed, Mohamed Diwan M; Tawa, Gregory; Wallqvist, Anders
A total of 2,010 blood samples inoculated into tryptic soy broth were examined for antibacterial activity by means of a bioassay plate seeded with Bacillus subtilis spores. The size of the zone of inhibition on this plate was indicative of the degree of antibacterial activity. Current antibiotic therapy was confirmed by examination of chart records. Of the 2,010 blood cultures tested, 147 (7.3%) contained detectable levels of antibiotics; of these 147, 14 (9.5%) yielded growth of bacteria, and 133 (90.5%) remained negative. When the Antibiotic Removal Device (Marion Scientific, Div. Marion Laboratories, Inc., Kansas City, Mo.) was used, it eliminated the antibacterial activity but did not improve the recovery of bacteria from these cultures. Only bacteria resistant to the respective antibiotic were recovered from blood cultures that showed high levels of antibacterial activity (beta-lactam antibiotics, greater than 0.60 micrograms/ml; aminoglycosides, greater than 2 micrograms/ml; and tetracycline, greater than 4 micrograms/ml). Blood cultures showing low levels of antibacterial activity yielded both resistant and susceptible bacteria.
Rodriguez, F; Lorian, V
Background\\/Aim: Norfloxacin prophylaxis decreases the incidence of bacterial infections in high-risk cirrhotic patients, but may promote the development of quinolone-resistant gram-negative bacteria in stools, and eventually lead to infections due to these bacteria. The aim of the study was to evaluate the prevalence of quinolone-resistant strains of E.coli in stools on admission, and the characteristics of any nosocomial infections.Methods: Eighty-three
José Ramón Aparicio; José Such; Sonia Pascual; Angeles Arroyo; Joaquín Plazas; Eva Girona; Ana Gutiérrez; Félix de Vera; José Maria Palazón; Fernando Carnicer; Miguel Pérez-Mateo
Garenoxacin is a novel quinolone that does not have a fluorine substituent at the C-6 position in the quinoline ring. Garenoxacin or 14C-garenoxacin was intravenously or orally administered to rats, dogs, and monkeys. Metabolic profiles and pharmacokinetic parameters were investigated focusing on the species differences and the allometric scaling of pharmacokinetic parameters. Garenoxacin was well absorbed following oral administration then underwent phase II metabolism in all species tested. Major metabolites of garenoxacin were the sulfate of garenoxacin (M1) and glucuronide (M6). Oxidative metabolites were present in very minor concentrations in all species tested. Another minor route of metabolism was the formation of the carbamoyl glucuronide. Garenoxacin is characterized across species by the observation that it circulates systemically, is excreted renally as unchanged drug, and is metabolized to M1 and M6, which are excreted specifically into the bile. The total clearances (CL) were 12.1, 2.43, and 3.39 ml/min/kg for rats, dogs, and monkeys, respectively. The distribution volume values of garenoxacin (Vss) were 0.88, 1.29, and 0.96 l/kg for rats, dogs, and monkeys, respectively. In all animals tested, the extrarenal clearance was larger than the renal clearance, and neither of the clearances was limited by blood flow. Despite these conditions, garenoxacin showed a good correlation for CL and Vss for allometric interspecies scaling. PMID:14570774
Hayakawa, Hiroyoshi; Fukushima, Yoko; Kato, Hiroshi; Fukumoto, Hiroyuki; Kadota, Takumi; Yamamoto, Hiroyuki; Kuroiwa, Hiroyuki; Nishigaki, Junko; Tsuji, Akira
A set of 37 doxycycline neoglycosides were prepared, mediated via a C-9 alkoxyamino-glycyl-based spacer reminiscent of that of tigecycline. Subsequent in vitro antibacterial assays against representative drug-resistant Gram negative and Gram positive strains revealed a sugar-dependent activity profile and one doxycycline neoglycoside, the 2'-amino-?-d-glucoside conjugate, to rival that of the parent pharmacophore. In contrast, the representative tetracycline-susceptible strain E. coli 25922 was found to be relatively responsive to a range of doxycycline neoglycosides. This study also extends the use of aminosugars in the context of neoglycosylation via a simple two-step strategy anticipated to be broadly applicable for neoglycorandomization. PMID:23987662
Zhang, Jianjun; Ponomareva, Larissa V; Marchillo, Karen; Zhou, Maoquan; Andes, David R; Thorson, Jon S
The problem of antibiotic resistance has eroded the usefulness of our arsenal of effective antibiotics. There is a need for new strategies to discover and develop new, effective drugs. The advent of the microbial genomics era has provided a wealth of information on a variety of microorganisms. This has allowed the identification and/or validation of a number of gene products that could serve as targets for the discovery of novel antibacterial agents. New genetic techniques and approaches have arisen in an attempt to exploit this newly available genomic data. Both random and targeted gene disruption efforts have proven effective in this process. Many of these methods would have been difficult to accomplish without DNA sequence and bioinformatics analyses. Several targets have been selected to further characterize and screen for inhibitors and one has yielded two clinical candidates. PMID:16412986
Pucci, Michael J
In 2005, a US Food and Drug Administration Nonprescription Drug Advisory Committee (NDAC) review of consumer antiseptic handwash product studies concluded that the data regarding existing products failed to demonstrate any association between specific log reductions of bacteria achieved by antiseptic handwashing and reduction of infection. The NDAC recommended that consumer antibacterial handwashing products should demonstrate a reduction in infection compared with non-antibacterial handwash products. In response to the NDAC review, a consumer product industry-sponsored expert panel meeting was held in October 2007 to review new methods for assessing the efficacy of antibacterial handwashes. The expert panel reviewed a newly proposed model for linking the effectiveness of antibacterial handwashing to infection reduction and made recommendations for conducting future studies designed to demonstrate the efficacy of antibacterial handwash formulations. The panel concluded that using the surrogate infection model to demonstrate efficacy has a sound scientific basis, that the use of Shigella flexneri as a test organism coupled with a modified hand contamination procedure is supported by published data, and that the model represents a realistic test for the efficacy of consumer antibacterial handwash products. This article summarizes the expert panel's deliberations, conclusions, and recommendations. PMID:22300895
Boyce, John M; Dupont, Herbert L; Massaro, Joseph; Sack, David; Schaffner, Donald W
Pseudomonas quinolone signal (PQS), 2-heptyl-3-hydroxy-4-quinolone, is an intercellular alkyl quinolone signaling molecule produced by the opportunistic pathogen Pseudomonas aeruginosa. Alkyl quinolone signaling is an atypical system that, in P. aeruginosa, controls the expression of numerous virulence factors. PQS is synthesized from the tryptophan pathway intermediate, anthranilate, which is either derived from the kynurenine pathway or from an alkyl quinolone specific anthranilate synthase encoded by phnAB. Anthranilate is converted to PQS by the enzymes encoded by the pqsABCDE operon and pqsH. PqsA forms an activated anthraniloyl-CoA thioester that shuttles anthranilate to the PqsD active site where it is transferred to Cys112 of PqsD. In the only biochemically characterized reaction, a condensation then occurs between anthraniloyl-PqsD and malonyl-CoA or malonyl-ACP, a second PqsD substrate, forming 2,4-dihydroxyquinoline (DHQ). The role PqsD plays in the biosynthesis of other alkyl quinolones, such as PQS, is unclear though it has been reported to be required for their production. No evidence however, exists that DHQ is a PQS precursor. Here we present a structural and biophysical characterization of PqsD that includes several crystal structures of the enzyme including that of the PqsD-anthranilate covalent intermediate and the inactive Cys112Ala active site mutant in complex with anthranilate. The structure reveals that PqsD is structurally similar to the FabH and chalcone synthase families of fatty acid and polyketide synthases. The crystallographic asymmetric unit contains a PqsD dimer. The PqsD monomer is composed of two nearly identical ~170 residue ????? domains. The structures show anthranilate-liganded Cys112 is positioned deep in the protein interior at the bottom of a ~15 Ĺ long channel while a second anthraniloyl-CoA molecule is waiting in the cleft leading to the protein surface. Cys112, His257, and Asn287 form the FabH-like catalytic triad of PqsD. The C112A mutant is inactive although it still reversibly binds anthraniloyl-CoA. The covalent complex between anthranilate and Cys112 clearly illuminates the orientation of key elements of the PqsD catalytic machinery and represents a snapshot of a key point in the catalytic cycle.
Bera, Asim K.; Atanasova, Vesna; Robinson, Howard; Eisenstein, Edward; Coleman, James P.; Pesci, Everett C.; Parsons, James F.
Several novel metal–quinolone compounds have been synthesized and characterized by analytical, spectroscopic and X-ray diffraction methods. The crystal structure of the four compounds, Na2[(Cd(Cx)3)(Cd(Cx)3(H2O))]·12H2O, [Co(Cp)2(H2O)2]·9H2O, [Zn(Cp)2(H2O)2]·8H2O and [Cd(HCp)2(Cl)2]·4H2O, is presented and discussed: HCx=1-ethyl-1,4-dihydro-4-oxo(1,3)-dioxolo(4,5-g)cinnoline-3-carboxylic acid and HCp=1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid. In all these compounds the quinolone acts as a bidentate chelate ligand that binds through one carboxylate oxygen atom and the exocyclic
M. P López-Gresa; R Ortiz; L Perelló; J Latorre; M Liu-González; S Garc??a-Granda; M Pérez-Priede; E Cantón
The in vitro activities of five new quinolones (clinafloxacin [CI-960 or PD-127391], BAY Y 3118, E-4868, E-5065, and E-5068) against 100 Bacteroides fragilis group bacterial isolates were compared with those of ciprofloxacin, ofloxacin, and sparfloxacin. Overall, E-5068 was the most active in vitro (MIC for 90% of isolates tested [MIC90], 0.25 microgram/ml); this was followed by clinafloxacin and BAY Y 3118 (MIC90, 0.5 microgram/ml). Ciprofloxacin, sparfloxacin, and ofloxacin were the least active (MIC90s, 64, 16, and 16 micrograms/ml, respectively). B. fragilis and Bacteroides caccae were more susceptible than the other members of the B. fragilis group to all of the quinolones tested.
Borobio, M V; Conejo, M; Ramirez, E; Suarez, A I; Perea, E J
We searched for plasmid-mediated quinolone resistance determinants of the Qnr type in several water samples collected at diverse locations from the Seine River (Paris, France). The qnrS2 genes were identified from Aeromonas punctata subsp. punctata and A. media. The qnrS2 gene was located on IncU-type plasmids in both isolates, which resulted in increased MIC values of quinolones and fluoroquinolones, once they were transferred into Escherichia coli. The qnrS2 gene identified in A. punctata was part of novel genetic structure corresponding to a mobile insertion cassette element. This identification of plasmid-mediated qnr genes outside Enterobacteriaceae underlines a possible diffusion of those resistance determinants within gram-negative rods.
Cattoir, Vincent; Poirel, Laurent; Aubert, Camille; Soussy, Claude-James
A set of 6-substituted quinolone nucleosides linked to aniline or phenol via N or O heteroatom-bridges presenting new compounds were synthesized by palladium-catalyzed Buchwald-Hartwig cross-coupling reactions. 6-Bromoquinolone nucleoside precursors, being protected by either benzoyl or TBDMS protecting groups on the ribose moiety, were subjected to different Buchwald-Hartwig conditions as the key step. Defined deprotection steps led, in good yields, to the final target compounds that carry, in position 3, either ester, acid, or amide functions. Thus, a series of novel quinolone nucleoside derivatives was obtained via a convergent synthesis route. Biological tests in human chronic myelogenous leukemia K562 cells exerted an efficient antiproliferative activity for two of them without induction of differentiation. These novel nucleosides deserve further experiments to determine their antiproliferative effects on other CML cell lines. PMID:24105761
Wicke, Lena; Engels, Joachim W; Gambari, Roberto; Saab, Antoine M
A four-year prospective study was carried out to determine the incidence and rate of development of resistance by common urinary tract infection (UTI) pathogens to quinolone antimicrobial agents. Results show that there is high intrinsic resistance to the quinolones among strains of Pseudomonas aeruginosa (43.4%), Escherichia coli (26.3%), and Proteus spp. (17.1%). Over four years, rising rates of resistance were observed in P. aeruginosa (14.6% increase), Staphylococcus aureus (9.8%), and E. coli (9.7%). The highest potency was exhibited by ciprofloxacin (91.2%), levofloxacin (89.2%), and moxifloxacin (85.1%), while there were high rates of resistance to nalidixic acid (51.7%) and pefloxacin (29.0%). Coliforms, particularly E. coli (>45%), remain the most prevalent causative agents of UTI while females within the age range of 20-50 years were most vulnerable to UTI. PMID:20360901
Omigie, Orhiosefe; Okoror, Lawrence; Umolu, Patience; Ikuuh, Gladys
Fluoroquinolones which are in use since 1986, are effective agents both against gram-positive and gram-negative bacteria. Quinolones show bactericidal effect as a result of inhibition of DNA gyrase and topoisomerase IV enzymes. Main quinolone resistance mechanisms are chromosomal mutations in these enzymes and decreased intracellular accumulation due to efflux pumps or decreased membrane uptake. Recently a new quinolone resistance mechanism mediated by plasmids has been defined. These plasmids carry genes called as qnr. Qnr genes do not cause quinolone resistance but they cause decreased quinolone susceptibility and lead to higher minimum inhibitory concentrations. Currently there are qnrA, qnrB, qnrC, qnrD and qnrS genes. This study was aimed to investigate the presence of plasmid-mediated quinolone resistance determinants in Enterobacteriaceae isolates collected from four different centers in Turkey. A total of 647 isolates (387 from Trabzon, Black Sea region; 82 from Canakkale, Trace region; 96 from Ankara, Central Anatolia region; 82 from Tokat, Black Sea region) belonging to the Enterobacteriaceae family collected between May-July 2009, were included in the study. Presence of qnrA, qnrB, qnrS and qnrC genes were investigated by multiplex polymerase chain reaction (PCR) method and confirmed by gene sequencing. The results of the PCR amplification revealed that 2 isolates were positive for qnrA, 12 isolates were positive for qnrB, 4 isolates were positive for qnrC and 10 isolates were positive for qnrS. However, the number of positive strains decreased with the use of gene sequencing, and this method led to the identification of qnrA1 in two isolates [Enterobacter cloacae (code. 796), Salmonella group B (code. 491)], qnrB1 in two isolates [Salmonella group B (code. 491), Citrobacter freundii (code. 768)], qnrB6 in one isolate [Escherichia coli (code. CC1800)], qnrB9 in one isolate [E.coli (code. CC1873)], qnrB24 in one isolate [Citrobacter koseri (code. MP5200)], qnrB27 in one isolate [C.freundii (code. 842)], qnrS1 in two isolates [E.coli (code. CC1705), E.coli (code.159)] and qnrB2 in one isolate [E.coli (code. 843)]. One of the isolates that carried the qnr gene was ciprofloxacin-resistant and two isolates were nalidixic-acid resistant. Transferable quinolone resistance due to the dissemination of qnr genes may have important impacts in terms of infection control and treatment problems. Survey of plasmid mediated quinolone resistance will help to determine the size of the issue and guide the measures that should be taken to avoid escalation of resistance and dissemination problem. PMID:22951649
Coban, Ahmet Y?lmaz; Nohut, Okan Kadir; Tanr?verdi Çayc?, Yeliz; Bayramo?lu, Gülçin; Pirinççiler, Müjgan; Cetinkaya, Ebru; Cekiç Cihan, Ci?dem; Bozdo?an, Bülent; Durup?nar, Belma
A four-year prospective study was carried out to determine the incidence and rate of development of resistance by common urinary tract infection (UTI) pathogens to quinolone antimicrobial agents. Results show that there is high intrinsic resistance to the quinolones among strains of Pseudomonas aeruginosa (43.4%), Escherichia coli (26.3%), and Proteus spp. (17.1%). Over four years, rising rates of resistance were observed in P. aeruginosa (14.6% increase), Staphylococcus aureus (9.8%), and E. coli (9.7%). The highest potency was exhibited by ciprofloxacin (91.2%), levofloxacin (89.2%), and moxifloxacin (85.1%), while there were high rates of resistance to nalidixic acid (51.7%) and pefloxacin (29.0%). Coliforms, particularly E. coli (>45%), remain the most prevalent causative agents of UTI while females within the age range of 20–50 years were most vulnerable to UTI.
Omigie, Orhiosefe; Okoror, Lawrence; Umolu, Patience; Ikuuh, Gladys
Pseudomonas, Burkholderia and Alteromonas species produce diverse 2-alkyl-4-quinolones (AHQs) which inhibit the growth of bacteria, algae and phytoplankton, chelate iron, modulate mammalian host immune defences and act as quorum-sensing (QS) signal molecules. To facilitate the detection, identification and quantification of the major Pseudomonas aeruginosa AHQs 2-heptyl-3-hydroxy-4-quinolone (PQS) and 2-heptyl-4-quinolone (HHQ) we developed two different AHQ biosensors. These were constructed by introducing either a lecA::luxCDABE or a pqsA::luxCDABE reporter gene fusion into a P. aeruginosa pqsA mutant which cannot synthesize AHQs. While both biosensors responded similarly to PQS (EC(50) 18 +/- 4 microM), the pqsA::luxCDABE biosensor was most sensitively activated by HHQ (EC(50) 0.44 +/- 0.1 microM). This biosensor was also activated albeit less sensitively by (i) PQS analogues with alkyl chains varying from C1 to C11, (ii) HHQ analogues with C9 and C11 alkyl chains and (iii) 2-heptyl-4-hydroxyquinoline-N-oxide (HHQNO). The AHQ biosensor also responded differentially to the AHQs present in cell free culture supernatants prepared from PAO1 and isogenic strains carrying mutations in genes (pqsA, pqsH, lasR, lasI, rhlR, rhlI) known to influence AHQ production. The AHQ profiles of P. aeruginosa strains was also evaluated by overlaying thin layer chromatogram (TLC) plates with the pqsA::luxCDABE biosensor. In PAO1, three major bioluminescent spots were observed which correspond to PQS, HHQ and a mixture of 2 nonyl-4-quinolone and HHQNO. We also noted that on TLC plates the biosensor not only produced bioluminescence in response to AHQs but also the green pigment, pyocyanin which offers an alternative visual indicator for AHQ production. PMID:17922753
Fletcher, Matthew P; Diggle, Stephen P; Crusz, Shanika A; Chhabra, Siri Ram; Cámara, Miguel; Williams, Paul
The reaction of triethylaluminum with stereoisomeric 2,7-dimethyl- and 1,2,7-trimethyldecahydro-4-quinolones and their 7-tert-butyl-substituted analogs was studied. The reaction of triethylaluminum with ketones that have an equatorial 2-CH3 group proceeds in two directions — reduction of the carbonyl group to an alcohol group and alkylation to give tertiary 4-ethyl-substituted alcohols — in benzene. depending on the reagent ratio. The stereochemistry of the
A. A. Akhrem; L. I. Ukhova; A. N. Sergeeva
A series of substituted 3,4-dihydro-2-quinolone glycogen phosphorylase inhibitors, which have potential as antidiabetic agents, is described. Initial members of the series showed good enzyme inhibitory potency but poor physical properties. Optimisation of the 1-substituent led to 2,3-dihydroxypropyl compounds which showed good in vitro potency and improved physical properties, together with good DMPK profiles and acute in vivo efficacy in a
Alan M. Birch; Peter W. Kenny; Nikos G. Oikonomakos; Ludovic Otterbein; Paul Schofield; Paul R. O. Whittamore; Dave P. Whalley
The epidemiology of quinolone resistance and the concomitant resistance to other antibiotic classes was investigated in 445\\u000a Klebsiella pneumoniae and 238 Klebsiella oxytoca isolates. Decreased susceptibility to ciprofloxacin was found in 7.2% and 3.4% of these two species, respectively. Ciprofloxacin\\u000a resistance was significantly linked to ceftazidime resistance, the hallmark of extended-spectrum ?-lactamase production, as\\u000a well as to resistance to all
S. Brisse; D. Milatovic; A. C. Fluit; J. Verhoef; F.-J. Schmitz
The alternative sigma factor 54 has been implicated in diverse functions within the cells. In this study, we have constructed an rpoN mutant of Pseudomonas aeruginosa and investigated its importance as a target for antimicrobial agents, such as quinolones and carbapenems. The stationary-phase cells of the rpoN mutant displayed a survival rate approximately 15 times higher than that of the
Darija Viducic; Tsuneko Ono; Keiji Murakami; Mikiko Katakami; Heni Susilowati; Yoichiro Miyake
Uropathogenic strains of E. coli isolated from urine of patients with urinary tract infections were tested for antibiotic sensitivity using bio-Merieux kits\\u000a and ATB-UR 5 expression system. The virulence of strains was evaluated by serum bactericidal assay, macrophage “killing” and\\u000a bacterial adhesive tests. Survival capability of strains was assessed under starvation in saline. The results showed that\\u000a quinolone-resistant uropathogenic strains
Georgi Slavchev; Nadya Markova
To enhance the antimicrobial spectrum of the quinolones against anaerobic organisms and gram-positive bacteria, we investigated in two studies the parenteral combinations of ciprofloxacin (200 mg) and ofloxacin (200 mg) with metronidazole (500 mg) or clindamycin (600 mg) and the oral combinations of enoxacin (400 mg) and fleroxacin (400 mg) with metronidazole (400 mg), clindamycin (300 mg), or ornidazole (500 mg) (only with fleroxacin). The pharmacokinetics and serum bactericidal activities (SBAs) against 5 aerobic and 2 anaerobic species (total, 58 strains) were determined in two groups of 10 healthy volunteers by using a randomized crossover study design. The additions of metronidazole, clindamycin, and ornidazole did not affect the pharmacokinetics of the quinolones. The combination of clindamycin with ciprofloxacin, ofloxacin, and, to a lesser extent, fleroxacin resulted in an increase of the SBA against gram-positive strains (mean peak titers): Staphylococcus aureus, ciprofloxacin alone, 1:5.5; ciprofloxacin-clindamycin, 1:19.9; ofloxacin alone, 1:3.6; ofloxacin-clindamycin, 1:17.5; fleroxacin alone, 1:4.3; fleroxacin-clindamycin, 1:8.1; Streptococcus pneumoniae (fleroxacin and enoxacin were not tested), ciprofloxacin alone, 1:2.0; ciprofloxacin-clindamycin, 1:53; ofloxacin alone, 1:2.6; and ofloxacin-clindamycin, 1:49.2. The high SBA of quinolones against gram-negative bacteria was not affected by the combinations; however, relatively low activities against Pseudomonas aeruginosa were detected. In general, against anaerobic bacteria, low bactericidal activities were determined in both studies (mean peak titers ranged from 1:2.1 to 1:3.1; mean trough titers range from 1:2.0 to 1:2.9). In clinical settings with severe mixed infections, a parenteral therapy consisting of modern quinolones together with clindamycin or imidazole derivatives seems to be active and offers no obvious interactions.
Boeckh, M; Lode, H; Deppermann, K M; Grineisen, S; Shokry, F; Held, R; Wernicke, K; Koeppe, P; Wagner, J; Krasemann, C
Development of resistance to nalidixic acid, norfloxacin and ciprofloxacin was observed in five patients withCampylobacter jejuni orCampylobacter coli infection. From all these patients nalidixic acid- and quinolone-susceptible strains were isolated initially, whereas after therapy with norfloxacin or ciprofloxacin strains resistant to these antibiotics were found.Campylobacter strains from the same patient always belonged to the same species and, with the exception
H. Adler-Mosca; J. Lüthy-Hottenstein; G. Martinetti Lucchini; A. Burnens; M. Altwegg
Geraniin and gallic acid were isolated from the alcohol extract of the aerial parts of Erodium glaucophyllum (Geraniaceae). The identity of the compounds was verified through different physical and spectrometric methods. The antibacterial and antifungal activity of geraniin is presented. PMID:14577629
Gohar, Ahmed A; Lahloub, Mohammed E; Niwa, Masatake
We report a recent case in which ciprofloxacin-resistant Shigella flexneri was isolated from a 23-yr-old female patient with a history of travel to India. Prior to her admission to our internal medicine department, she experienced symptoms of high fever and generalized weakness from continuous watery diarrhea that developed midway during the trip. S. flexneri was isolated from the stool culture. Despite initial treatment with ciprofloxacin, the stool cultures continued to show S. flexneri growth. In the susceptibility test for antibiotics of the quinolone family, the isolate showed resistance to ciprofloxacin (minimum inhibitory concentration [MIC], 8 µg/mL), norfloxacin (MIC, 32 µg/mL), ofloxacin (MIC, 8 µg/mL), nalidixic acid (MIC, 256 µg/mL), and intermediate resistance to levofloxacin (MIC, 4 µg/mL). In molecular studies for quinolone resistance related genes, plasmid borne-quinolone resistance genes such as qnrA, qnrB, qnrS, aac(6')-Ib-cr, qepA, and oqxAB were not detected. Two mutations were observed in gyrA (248C?T, 259G?A) and 1 mutation in parC (239G?T). The molecular characteristics of the isolated S. flexneri showed that the isolate was more similar to the strains isolated from the dysentery outbreak in India than those isolated from Korea. PMID:22950074
Jeon, You La; Nam, You-sun; Lim, Gayoung; Cho, Sun Young; Kim, Yun-Tae; Jang, Ji-Hyun; Kim, Junyoung; Park, Misun; Lee, Hee Joo
The gyrA gene mutations associated with quinolone resistance were determined in 21 epidemiologically unrelated clinical isolates of Acinetobacter baumannii. Our studies highlight the conserved sequences in the quinolone resistance-determining region of the gyrA gene from A. baumannii and other bacteria. All 15 isolates for which the MIC of ciprofloxacin is > or = 4 micrograms/ml showed a change at Ser-83 to Leu. Six strains for which the MIC of ciprofloxacin is 1 microgram/ml did not show any change at Ser-83, although a strain for which the MIC of ciprofloxacin is 1 microgram/ml exhibited a change at Gly-81 to Val. Although it is possible that mutations in other locations of the gyrA gene, the gyrB gene, or in other genes may also contribute to the modulation of the MIC level, our results suggest that a gyrA mutation at Ser-83 is associated with quinolone resistance in A. baumannii.
Vila, J; Ruiz, J; Goni, P; Marcos, A; Jimenez de Anta, T
Antibiotic susceptibility testing of the rickettsial Q fever agent Coxiella burnetii was performed by using persistently infected L929 fibroblast cells. The efficacies of a variety of antibiotics with different metabolic targets were tested and compared. The most effective antibiotics in bringing about the elimination of the parasite from infected cells included several quinolone compounds and rifampin. Of the quinolone compounds tested, difloxacin (A-56619) was the most effective, followed by ciprofloxacin and oxolinic acid. These three quinolones were apparently rickettsiacidal. After 48 h of exposure to microgram amounts of the compounds (ranging from 2 micrograms of difloxacin per ml to 5 micrograms of the other two antibiotics per ml), the number of intracellular parasites markedly declined; after 10 days of treatment, very few intracellular rickettsiae were detected. Rifampin (1 microgram/ml) was also very effective in eliminating the parasites. Some of the 13 other antibiotics tested that were somewhat effective included chloramphenicol, doxycycline, and trimethoprim. The persistently infected L929 cells were found to provide a convenient system for the relatively rapid determination of the susceptibility of C. burnetii to antibiotics. Images
Yeaman, M R; Mitscher, L A; Baca, O G
Cancer chemotherapy was introduced at the same time as antibacterial chemotherapy but has not been nearly such a success.\\u000a However, there is a growing optimism in oncology today due to the introduction of several more or less target-specific drugs\\u000a as complements to the conventional cytotoxic drugs introduced half a century ago. The success in the treatment of chronic\\u000a myelogenous leukemia
The synthesis and evaluation of novel azetidine lincosamides 1 are described. Eleven new (3-trans-alkyl)azetidine-2-carboxylic acids were synthesized via alkylation of N-TBS-4-oxo-azetidine-2-carboxylic acid and subsequent elaboration then coupled to 7-chloro-1-methylthio-lincosamine. The resulting lincosamides differ from the drug clindamycin in both the size of the ring and the position\\/structure of the alkyl side-chain. SAR within the series was explored with attention to
Hardwin O’Dowd; Jason G. Lewis; Joaquim Trias; Rumi Asano; Johanne Blais; Sara L. Lopez; Craig K. Park; Charlotte Wu; Wen Wang; Mikhail F. Gordeev
The antibacterial activities of DK-507k, a novel quinolone, were compared with those of other quinolones: ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, sitafloxacin, and garenoxacin (BMS284756). DK-507k was as active as sitafloxacin and was as active as or up to eightfold more active than gatifloxacin, moxifloxacin, and garenoxacin against Streptococcus pneumoniae, methicillin-susceptible and methicillin-resistant Staphylococcus aureus, and coagulase-negative staphylococci. DK-507k was as active as or 4-fold more active than garenoxacin and 2- to 16-fold more active than gatifloxacin and moxifloxacin against ciprofloxacin-resistant strains of S. pneumoniae, including clinical isolates and in vitro-selected mutants with known mutations. DK-507k inhibited all ciprofloxacin-resistant strains of S. pneumoniae at 1 microg/ml. A time-kill assay with S. pneumoniae showed that DK-507k was more bactericidal than gatifloxacin and moxifloxacin. The activities of DK-507k against most members of the family Enterobacteriaceae were comparable to those of ciprofloxacin and equal to or up to 32-fold higher than those of gatifloxacin, levofloxacin, moxifloxacin, and garenoxacin. DK-507k was fourfold less active than sitafloxacin and ciprofloxacin against Pseudomonas aeruginosa, while it was two to four times more potent than levofloxacin, gatifloxacin, moxifloxacin, and garenoxacin against P. aeruginosa. In vivo, intravenous treatment with DK-507k was more effective than that with gatifloxacin and moxifloxacin against systemic infections caused by S. aureus, S. pneumoniae, and P. aeruginosa in mice. In a mouse model of pneumonia due to penicillin-resistant S. pneumoniae, DK-507k administered subcutaneously showed dose-dependent efficacy and eliminated the bacteria from the lungs, whereas gatifloxacin and moxifloxacin had no significant efficacy. Oral treatment with DK-507k was slightly more effective than that with ciprofloxacin in a rat model of foreign body-associated urinary tract infection caused by a P. aeruginosa isolate for which the MIC of DK-507k was fourfold higher than that of ciprofloxacin. Oral administration of DK-507k to rats achieved higher peak concentrations in serum and higher concentrations in cumulative urine than those achieved with ciprofloxacin. These data indicate the potential advantages of DK-507k over other quinolones for the treatment of a wide range of community-acquired infections. PMID:14638477
Otani, Tsuyoshi; Tanaka, Mayumi; Ito, Emi; Kurosaka, Yuichi; Murakami, Yoichi; Onodera, Kiyomi; Akasaka, Takaaki; Sato, Kenichi
The antibacterial activities of DK-507k, a novel quinolone, were compared with those of other quinolones: ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, sitafloxacin, and garenoxacin (BMS284756). DK-507k was as active as sitafloxacin and was as active as or up to eightfold more active than gatifloxacin, moxifloxacin, and garenoxacin against Streptococcus pneumoniae, methicillin-susceptible and methicillin-resistant Staphylococcus aureus, and coagulase-negative staphylococci. DK-507k was as active as or 4-fold more active than garenoxacin and 2- to 16-fold more active than gatifloxacin and moxifloxacin against ciprofloxacin-resistant strains of S. pneumoniae, including clinical isolates and in vitro-selected mutants with known mutations. DK-507k inhibited all ciprofloxacin-resistant strains of S. pneumoniae at 1 ?g/ml. A time-kill assay with S. pneumoniae showed that DK-507k was more bactericidal than gatifloxacin and moxifloxacin. The activities of DK-507k against most members of the family Enterobacteriaceae were comparable to those of ciprofloxacin and equal to or up to 32-fold higher than those of gatifloxacin, levofloxacin, moxifloxacin, and garenoxacin. DK-507k was fourfold less active than sitafloxacin and ciprofloxacin against Pseudomonas aeruginosa, while it was two to four times more potent than levofloxacin, gatifloxacin, moxifloxacin, and garenoxacin against P. aeruginosa. In vivo, intravenous treatment with DK-507k was more effective than that with gatifloxacin and moxifloxacin against systemic infections caused by S. aureus, S. pneumoniae, and P. aeruginosa in mice. In a mouse model of pneumonia due to penicillin-resistant S. pneumoniae, DK-507k administered subcutaneously showed dose-dependent efficacy and eliminated the bacteria from the lungs, whereas gatifloxacin and moxifloxacin had no significant efficacy. Oral treatment with DK-507k was slightly more effective than that with ciprofloxacin in a rat model of foreign body-associated urinary tract infection caused by a P. aeruginosa isolate for which the MIC of DK-507k was fourfold higher than that of ciprofloxacin. Oral administration of DK-507k to rats achieved higher peak concentrations in serum and higher concentrations in cumulative urine than those achieved with ciprofloxacin. These data indicate the potential advantages of DK-507k over other quinolones for the treatment of a wide range of community-acquired infections.
Otani, Tsuyoshi; Tanaka, Mayumi; Ito, Emi; Kurosaka, Yuichi; Murakami, Yoichi; Onodera, Kiyomi; Akasaka, Takaaki; Sato, Kenichi
DC-159a is a new 8-methoxy fluoroquinolone that possesses a broad spectrum of antibacterial activity, with extended activity against gram-positive pathogens, especially streptococci and staphylococci from patients with community-acquired infections. DC-159a showed activity against Streptococcus spp. (MIC90, 0.12 ?g/ml) and inhibited the growth of 90% of levofloxacin-intermediate and -resistant strains at 1 ?g/ml. The MIC90s of DC-159a against Staphylococcus spp. were 0.5 ?g/ml or less. Against quinolone- and methicillin-resistant Staphylococcus aureus strains, however, the MIC90 of DC-159a was 8 ?g/ml. DC-159a was the most active against Enterococcus spp. (MIC90, 4 to 8 ?g/ml) and was more active than the marketed fluoroquinolones, such as levofloxacin, ciprofloxacin, and moxifloxacin. The MIC90s of DC-159a against Haemophilus influenzae, Moraxella catarrhalis, and Klebsiella pneumoniae were 0.015, 0.06, and 0.25 ?g/ml, respectively. The activity of DC-159a against Mycoplasma pneumoniae was eightfold more potent than that of levofloxacin. The MICs of DC-159a against Chlamydophila pneumoniae were comparable to those of moxifloxacin, and DC-159a was more potent than levofloxacin. The MIC90s of DC-159a against Peptostreptococcus spp., Clostridium difficile, and Bacteroides fragilis were 0.5, 4, and 2 ?g/ml, respectively; and among the quinolones tested it showed the highest level of activity against anaerobic organisms. DC-159a demonstrated rapid bactericidal activity against quinolone-resistant Streptococcus pneumoniae strains both in vitro and in vivo. In vitro, DC-159a showed faster killing than moxifloxacin and garenoxacin. The bactericidal activity of DC-159a in a murine muscle infection model was revealed to be superior to that of moxifloxacin. These activities carried over to the in vivo efficacy in the murine pneumonia model, in which treatment with DC-159a led to bactericidal activity superior to those of the other agents tested.
Hoshino, Kazuki; Inoue, Kazue; Murakami, Yoichi; Kurosaka, Yuichi; Namba, Kenji; Kashimoto, Yoshinori; Uoyama, Saori; Okumura, Ryo; Higuchi, Saito; Otani, Tsuyoshi
Despite the success of genomics in identifying new essential bacterial genes, there is a lack of sustainable leads in antibacterial drug discovery to address increasing multidrug resistance. Type IIA topoisomerases cleave and religate DNA to regulate DNA topology and are a major class of antibacterial and anticancer drug targets, yet there is no well developed structural basis for understanding drug action. Here we report the 2.1 A crystal structure of a potent, new class, broad-spectrum antibacterial agent in complex with Staphylococcus aureus DNA gyrase and DNA, showing a new mode of inhibition that circumvents fluoroquinolone resistance in this clinically important drug target. The inhibitor 'bridges' the DNA and a transient non-catalytic pocket on the two-fold axis at the GyrA dimer interface, and is close to the active sites and fluoroquinolone binding sites. In the inhibitor complex the active site seems poised to cleave the DNA, with a single metal ion observed between the TOPRIM (topoisomerase/primase) domain and the scissile phosphate. This work provides new insights into the mechanism of topoisomerase action and a platform for structure-based drug design of a new class of antibacterial agents against a clinically proven, but conformationally flexible, enzyme class. PMID:20686482
Bax, Benjamin D; Chan, Pan F; Eggleston, Drake S; Fosberry, Andrew; Gentry, Daniel R; Gorrec, Fabrice; Giordano, Ilaria; Hann, Michael M; Hennessy, Alan; Hibbs, Martin; Huang, Jianzhong; Jones, Emma; Jones, Jo; Brown, Kristin Koretke; Lewis, Ceri J; May, Earl W; Saunders, Martin R; Singh, Onkar; Spitzfaden, Claus E; Shen, Carol; Shillings, Anthony; Theobald, Andrew J; Wohlkonig, Alexandre; Pearson, Neil D; Gwynn, Michael N
Garenoxacin is a new des-F(6)-quinolone with broad-spectrum activity against both gram-positive cocci and gram-negative bacilli. We used the neutropenic murine thigh infection model to characterize the time course of antimicrobial activity of garenoxacin and determine which pharmacokinetic-pharmacodynamic (PK-PD) parameter best correlated with efficacy. Serum drug levels following three fourfold-escalating single-dose levels of garenoxacin were measured by microbiologic assay. In vivo postantibiotic effects (PAEs) were determined after doses of 16 and 64 mg/kg of body weight. Mice had 106.5 to 106.7 CFU of Streptococcus pneumoniae strain ATCC 10813 or Staphylococcus aureus strain ATCC 33591 per thigh when they were treated for 24 h with garenoxacin at a dose of 4 to 128 mg/kg/day fractionated for 3-, 6-, 12-, and 24-hour dosing regimens. Nonlinear regression analysis was used to determine which PK-PD parameter best correlated with the measurement of CFU/thigh at 24 h. Pharmacokinetic studies yielded peak/dose values of 0.2 to 0.3, area under the concentration-time curve (AUC)/dose values of 0.1 to 0.5, and half-lives of 0.7 to 1.6 h. Garenoxacin produced in vivo PAEs of 1.4 to 8.2 h with S. pneumoniae ATCC 10813, 7.6 to >12.4 h with S. aureus ATCC 25923, and 0 to 1.5 h with Klebsiella pneumoniae ATCC 43816. The 24-h AUC/MIC ratio was the PK-PD parameter that best correlated with efficacy (R2 = 71 to 90% for the two organisms compared with 43 to 56% for the peak/MIC ratio and 47 to 75% for percent time above the MIC [% T>MIC]).In subsequent studies we used the neutropenic murine thigh infection model to determine if the magnitude of the AUC/MIC ratio needed for efficacy of garenoxacin varied among pathogens (including resistant strains). Mice had 105.9 to 107.2 CFU of 6 strains of S. aureus (2 methicillin resistant), 11 strains of S. pneumoniae (5 penicillin susceptible, 1 penicillin intermediate, and 5 penicillin resistant, and of the resistant strains, 3 were also ciprofloxacin resistant), and 4 gram-negative strains per thigh when treated for 24 h with 1 to 64 mg of garenoxacin per kg every 12 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic effect over 24 h. MICs ranged from 0.008 to 4 ?g/ml. The free drug 24-h AUC/MIC ratios for each static dose (2.8 to 128 mg/kg/day) varied from 8.2 to 145. The mean 24-h AUC/MIC ratios ± standard deviations for S. pneumoniae, S. aureus, and gram-negative strains were 33 ± 18, 81 ± 37, and 33 ± 30, respectively. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC ratio required for efficacy.
Andes, D.; Craig, W. A.
The norA gene cloned from chromosomal DNA of quinolone-resistant Staphylococcus aureus TK2566 conferred relatively high resistance to hydrophilic quinolones such as norfloxacin, enoxacin, ofloxacin, and ciprofloxacin, but only low or no resistance at all to hydrophobic ones such as nalidixic acid, oxolinic acid, and sparfloxacin in S. aureus and Escherichia coli. The 2.7-kb DNA fragment containing the norA gene had a long open reading frame coding for 388 amino acid residues with a molecular weight of 42,265, which was consistent with the experimental value of about 49,000 obtained on DNA-directed translation. The deduced NorA polypeptide has 12 hydrophobic membrane-spanning regions and is partly homologous to tetracycline resistance protein and sugar transport proteins. The uptake of a hydrophilic quinolone, enoxacin, by S. aureus harboring a plasmid carrying the norA gene was about 50% that by the parent strain lacking the plasmid, but it increased to almost the same level as that by the latter strain with carbonyl cyanide m-chlorophenyl hydrazone. On the other hand, the uptake of a hydrophobic quinolone, sparfloxacin, was similar in the two strains. These results suggest that the NorA polypeptide may constitute a membrane-associated active efflux pump of hydrophilic quinolones.
Yoshida, H; Bogaki, M; Nakamura, S; Ubukata, K; Konno, M
We induced 3 cell lines that were in vitro cultured from Lepidoptera with heat inactivated Escherichia coli DH5? to stimulate the antibacterial peptide followed by antibacterial activity assay, induction dynamic research and Tricine sodium\\u000a dodecyl sulfate-polyacrylamide gel electrophoresis (Tricine SDS-PAGE) experiment. The antibacterial activity of the induced\\u000a BTI-Tn-5B1 cell line was the highest, and the antibacterial activity increased gradually to
Rong Peng; Zhong Yang; Kaiyu Liu; Hanchao Yao; Hong Yang; Yanfang Cui; Huazhu Hong
An efficient LC method was developed for screening the presence of quinolones (QLs) – comprising fluoroquinolones (FQs) and acidic quinolones (AQs) – residues in various livestock and fishery products. Targeted analytes were for nine FQs of marbofloxacin (MAR), ofloxacin (OFL), norfloxacin (NOR), ciprofloxacin (CIP), enrofloxacin (ENR), danofloxacin (DAN), orbifloxacin (ORB), difloxacin (DIF) and sarafloxacin (SAR), and three AQs of oxolinic
N. Takeda; M. Gotoh; T. Matsuoka
Catharanthus roseus popularly known as Madagascar periwinkle is a potential source for anti-leukemic alkaloids. The present study aims to evaluate the possibility for the presence of novel bio-active compounds against pathogenic bacteria, as most of the pathogens develop drug resistance against commonly used antibiotics. To determine antibacterial activity, crude extracts from different parts of C. roseus were tested against bacterial
Background and the purpose of the study The purpose of this study was to prepare pegylated poly lactide-co-glycolide (PEG-PLGA) nanoparticles (NPs) loaded with roxithromycin (RXN) with appropriate physicochemical properties and antibacterial activity. Roxithromycin, a semi-synthetic derivative of erythromycin, is more stable than erythromycin under acidic conditions and exhibits improved clinical effects. Methods RXN was loaded in pegylated PLGA NPs in different drug;polymer ratios by solvent evaporation technique and characterized for their size and size distribution, surface charge, surface morphology, drug loading, in vitro drug release profile, and in vitro antibacterial effects on S. aureus, B. subtilis, and S. epidermidis. Results and conclusion NPs were spherical with a relatively mono-dispersed size distribution. The particle size of nanoparticles ranged from 150 to 200 nm. NPs with entrapment efficiency of up to 80.0±6.5% and drug loading of up to 13.0±1.0% were prepared. In vitro release study showed an early burst release of about 50.03±0.99% at 6.5 h and then a slow and steady release of RXN was observed after the burst release. In vitro antibacterial effects determined that the minimal inhibitory concentration (MIC) of RXN loaded PEG-PLGA NPs were 9 times lower on S. aureus, 4.5 times lower on B. subtilis, and 4.5 times lower on S. epidermidis compared to RXN solution. In conclusion it was shown that polymeric NPs enhanced the antibacterial efficacy of RXN substantially.
Twenty-one extracts from seven herbal drugs, Aristolochia trilobata (Aristolochiaceae) leaves and bark, Bursera simaruba (Burseraceae) bark, Guazuma ulmifolia (Sterculiaceae) bark, Hamelia patens (Rubiaceae) leaves and Syngonium podophyllum (Araceae) leaves and bark, used in traditional medicine of Belize (Central America) as deep and superficial wound healers, were evaluated for their anti-bacterial properties. Activity was tested against standard strains of Escherichia coli
A. Camporese; M. J. Balick; R. Arvigo; R. G. Esposito; N. Morsellino; F. De Simone; A. Tubaro
Preparative separation of quinolone alkaloids in Evodia rutaecarpa (Juss.) Benth was conducted by high performance counter-current chromatography (HPCCC) with a pair of two solvent systems consisting of n-hexane-methanol-water-acetic acid (2:1:1:0.2, v\\/v) and (5:4:2:0.1, v\\/v). Consequently, 31.78 mg 1-methyl-2-nonyl-4 (1H)-quinolone (I), 59.25 mg 1-methyl-2-(6-undecenyl)-4 (1H)-quinolone (II), 333.27 mg evocarpine (III), 101.13 mg 1-methyl-2-(6,9-pentadecadienyl)-4(1H)-quinolone (IV), 132.17 mg dihydroevocarpine (V), and 86.99 mg 1-methyl-2-(10-pentadecenyl)-4(1H)-quinolone (VI) were obtained from 1.3 g
Shijie Zhong; Haoye Ye; Aihua Peng; Jie Shi; Shichao He; Shucai Li; Xia Ye; Minghai Tang; Lijuan Chen
Plasmid pJSW101 derived from pUC19 and carrying the wild-type gyrA gene was found to be unstable in HM72, a quinolone-resistant (QR) clinical isolate of Escherichia coli, and resulted in no change in quinolone MICs. MICs determined in the presence of ampicillin to ensure plasmid presence, however, resulted in complementation. HM72 was proved to have a gyrA mutation based on the DNA sequence of a 418-bp fragment of gyrA. DNA sequencing identified a common mutation encoding Leu-83 as the cause of QR. To identify loci other than gyrA and nfxB contributing to QR in KF111b, zgh-3075::Tn10 (67 min) in CAG12152 was transduced into KF111b. Sixteen percent of the transductants had a fourfold decrease in norfloxacin MIC, indicating the presence of a locus, nfxD, which contributes to QR. Outcross of nfxD from DH151 (gyrA nfxB nfxD zgh-3075::Tn10) resulted in 8% of the KF130 gyrA, 2% of the EN226-3 gyrA, and none of the KL16 (wild-type) transductants, with a four- to eightfold increase in norfloxacin MIC. In the presence of ampicillin, the resistance of a gyrA nfxD double mutant, DH161 nfxD gyrA (from EN226-3), was fully complemented by gyrA+. Thus, gyrA+ plasmid complementation tests for QR may be falsely negative with plasmid instability, a difficulty which may be circumvented by maintenance of plasmid selection. In addition, if nfxD-like mutations occur in gyrA clinical isolates, a positive test may overestimate the level of resistance attributable to gyrA alone.
Soussy, C J; Wolfson, J S; Ng, E Y; Hooper, D C
We studied the evolution of resistance to quinolones in Escherichia coli from 1992 to 1997 in Barcelona, Spain. An increasing proportion of quinolone-resistant E. coli (QREC) infections was observed. QREC strains were more common in patients with nosocomial infections but also increased in patients with community-acquired infections (9% in 1992 to 17% in 1996). Seventy (12%) of 572 episodes of E. coli bacteremia were due to QREC. Factors significantly associated with QREC bacteremia were the presence of underlying disease, recent exposure to antibiotics, and bacteremia of unknown origin. In the multivariate analysis, only prior exposure to antimicrobial agents (P < 0.001; odds ratio [OR] = 2), specifically, to quinolones (P < 0.001; OR = 14), and the presence of a urinary catheter (P < 0.001; OR = 2) were significantly associated with QREC bacteremia. Among 16 QREC isolates from cultures of blood of community origin selected at random, 13 different pulsed-field gel electrophoresis patterns were recognized, showing the genetic diversity of these isolates and in turn indicating the independent emergence of QREC in the community. The prevalence of QREC in the feces of healthy people was unexpectedly high (24% in adults and 26% in children). A survey of the prevalence of QREC of avian and porcine origin revealed a very high proportion of QREC in animal feces (up to 90% of chickens harbored QREC). The high prevalence of QREC in the stools of healthy humans in our area could be linked to the high prevalence of resistant isolates in poultry and pork.
Garau, Javier; Xercavins, Mariona; Rodriguez-Carballeira, Monica; Gomez-Vera, Josep Ramon; Coll, Ignacio; Vidal, Dolors; Llovet, Teresa; Ruiz-Bremon, Ana
This study was done to investigate the antimicrobial potentiality of the marine algae collected from different coastal regions of Gujarat and screened for the same. Twenty-six marine algae belonging to Rhodophyceae, Chlorophyceae and Phaeophyceae were screened for their potential antibacterial activity against five clinically important bacterial strains, namely Bacillus cereus, Micrococcus flavus, Citrobacter freundii, Klebsiella pneumoniae and Pseudomonas testosterone. Acetone and methanol were used for extraction; and the extracted yield was more when the solvent used was methanol. The antibacterial activity was done by both Agar disc diffusion method and Agar ditch method. The five bacterial strains showed varied response towards marine algal extracts. The most susceptible bacteria was B. cereus followed by K. pneumoniae and C. freundii while the most resistant bacteria were M. flavus and P. testosteroni. Among the 26 algae screened, E. intestinalis was the most potent alga and thus, this alga was selected for further studies. E. intestinalis was extracted in petroleum ether, 1,4-dioxan, acetone, methanol and DMF, and their antibacterial activity was studied against the above-stated five bacterial strains using agar disc method. Maximum extractive value of E. intestinalis was in methanol (2.05%) and minimum was in acetone (0.38%). The most susceptible bacteria was K. pneumoniae and maximum antibacterial activity was shown by petroleum ether extract and minimum was shown by 1,4-dioxan extract. The most resistant bacteria were M. flavus and C. freundii. The MIC values of E. intestinalis extracts ranged from 2500-9.765 microg/0.5 ml against B. cereus and K. pneumoniae. From these results it is concluded that the acetone extract of E. intestinalis is the most potent extract and can be used as a lead molecule in drug discovery in inhibiting some of the bacterial strains. E. intestinalis can be used as a promising novel marine antimicrobial agent in the coming years. PMID:17594989
Nair, Ratish; Chabhadiya, Rajesh; Chanda, Sumitra
The in vitro activity of DX-619, a new des-F(6) quinolone, against anaerobic bacteria was evaluated. DX-619 showed potent activity against Bacteroides, Prevotella, Fusobacterium, Micromonas, Actinomyces, and Clostridium spp., with MIC50s/MIC90s of ?0.03 to 0.25/?0.03 to 1 ?g/ml, respectively. DX-619 was also active against imipenem-resistant Bacteroides spp., with MIC50s/MIC90s of 0.25/1 ?g/ml, respectively.
Tanaka, Kaori; Mikamo, Hiroshige; Nakao, Ken'ichi; Watanabe, Kunitomo
Pseudomonas aeruginosa secretes membrane vesicles (MVs) that deliver several virulence factors as a cargo. We found that indole and its derivative compounds, including 4-hydroxyindole, 5-hydroxyindole, 6-hydroxyindole and isatin, repress MV production significantly. These compounds also repressed the synthesis of Pseudomonas quinolone signal (PQS), which is one of the quorum-sensing signals that upregulate virulence gene expression and positively control MV production. Moreover, we showed that other bicyclic compounds, including 1-naphthol, 2-naphthol, 2,3-dihydroxynaphthalene, 1-aminonaphthalene and 8-quinolinol, significantly repress MV production and PQS synthesis. In conclusion, we provide new information about the chemical structures that inhibit P. aeruginosa virulence. PMID:20146747
Tashiro, Yosuke; Toyofuku, Masanori; Nakajima-Kambe, Toshiaki; Uchiyama, Hiroo; Nomura, Nobuhiko
Sixteen extracts, obtained from eight Brazilian plants of Annonaceae family, were screened for their antibacterial activity: Xylopia frutescens, X. aromatica, X. amazonica, X. benthamii, Annona ambotay, A. crassiflora, A. muricata and A. cherimolia. Amongst the investigated extracts, six showed antibacterial activity against at least one of the tested organisms at the concentration of 100?µg\\/mL. The most active extracts were those
Jacqueline A. Takahashi; Cássia R. Pereira; Lúcia P. S. Pimenta; Maria Amélia D. Boaventura; Luiz G. F. E Silva
The recent entry of products containing antibacterial agents into healthy households has escalated from a few dozen products in the mid-1990s to more than 700 today. Antibacterial products were developed and have been successfully used to prevent transmission of disease-causing microorganisms among patients, particularly in hospitals. They are now being added to products used in healthy households, even though an
Stuart B. Levy
The antibacterial activity of 31 chalcones was tested against bacterial strains, Bacillus cereus ATCC 11778, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, and Staphylococcus aureus ATCC 25923. Some of the tested chalcones showed fair to significant activity against Gram-positive bacteria. By comparison of the results obtained, the antibacterial activity can be related to features such as the presence of
Hugo Pereira Ávila; Elza de Fátima Albino Smânia; Franco Delle Monache; Artur Smânia
Chitosan nanoparticles, such as those prepared in this study, may exhibit potential antibacterial activity as their unique character. The purpose of this study was to evaluate the in vitro antibacterial activity of chitosan nanoparticles and copper-loaded nanoparticles against various microorganisms. Chitosan nanoparticles were prepared based on the ionic gelation of chitosan with tripolyphosphate anions. Copper ions were adsorbed onto the
Lifeng Qi; Zirong Xu; Xia Jiang; Caihong Hu; Xiangfei Zou
Antibacterial discovery research has been driven, medically, commercially and intellectually, by the need for new therapeutics that are not subject to the resistance mechanisms that have evolved to combat previous generations of antibacterial agents. This need has often been equated with the identification and exploitation of novel targets. But efforts towards discovery and development of inhibitors of novel targets have
Lynn L Silver
The aqueous and ethanol extracts prepared from some lichens species were evaluated for antibacterial activity against six standard strains (Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Klebsiella pneumoniae, Staphylococcus aureus and Staphylococcus epidermidis) and two environmental strains (Aeromonas) that were isolated from different lakes. The aqueous and ethanol extracts showed a variable range of antibacterial activity to both standard strains and
Ali Karagöz; Nihal Doruöz; Zuhal Zeybek; Ali Aslan
Among the aetiological agents of treatable sexually transmitted diseases (STDs), Neissseria gonorrhoeae is considered to be most important because of emerging antibiotic resistant strains that compromise the effectiveness of treatment of the disease - gonorrhoea. In most of the developing countries, treatment of gonorrhoea relies mainly on syndromic management rather than the aetiological based therapy. Gonococcal infections are usually treated with single-dose therapy with an agent found to cure > 95 per cent of cases. Unfortunately during the last few decades, N. gonorrhoeae has developed resistance not only to less expensive antimicrobials such as sulphonamides, penicillin and tetracyclines but also to fluoroquinolones. The resistance trend of N. gonorrhoeae towards these antimicrobials can be categorised into pre-quinolone, quinolone and post-quinolone era. Among the antimicrobials available so far, only the third-generation cephalosporins could be safely recommended as first-line therapy for gonorrhoea globally. However, resistance to oral third-generation cephalosporins has also started emerging in some countries. Therefore, it has become imperative to initiate sustained national and international efforts to reduce infection and misuse of antibiotics so as to prevent further emergence and spread of antimicrobial resistance. It is necessary not only to monitor drug resistance and optimise treatment regimens, but also to gain insight into how gonococcus develops drug resistance. Knowledge of mechanism of resistance would help us to devise methods to prevent the occurrence of drug resistance against existing and new drugs. Such studies could also help in finding out new drug targets in N. gonorrhoeae and also a possibility of identification of new drugs for treating gonorrhoea.
Patel, Achchhe Lal; Chaudhry, Uma; Sachdev, Divya; Sachdeva, Poonam Nagpal; Bala, Manju; Saluja, Daman
We studied the activities of clarithromycin and fluoroquinolones (gatifloxacin, sitafloxacin, levofloxacin) in combination with other antimycobacterial drugs against extracellular and intramacrophage Mycobacterium avium complex (MAC). Clarithromycin potentiated the activities of rifampicin and rifalazil against both extracellular and intramacrophage MAC. In contrast, all the test quinolones exhibited antagonistic effects against extracellular MAC when combined with either clarithromycin or rifamycins. Such an
Haruaki Tomioka; Chiaki Sano; Katsumasa Sato; Toshiaki Shimizu
Hydrogels are finding increased clinical utility as advances continue to exploit their favorable material properties. Hydrogels can be adapted for many applications, including surface coatings and drug delivery. Anti-infectious surfaces and delivery systems that actively destroy invading organisms are alternative ways to exploit the favorable material properties offered by hydrogels. Sterilization techniques are commonly employed to ensure the materials are non-infectious upon placement, but sterilization is not absolute and infections are still expected. Natural, anti-bacterial proteins have been discovered which have the potential to act as anti-infectious agents; however, the proteins are toxic and need localized release to have therapeutic efficacy without toxicity. In these studies, we explore the use of the glutathione s-transferase (GST) to anchor the bactericidal peptide, melittin, to the surface of poly(ethylene glycol) diacrylate (PEGDA) hydrogel microspheres. We show that therapeutic levels of protein can be anchored to the surface of the microspheres using the GST anchor. We compared the therapeutic efficacy of recombinant melittin released from PEGDA microspheres to melittin. We found that, when released by an activating enzyme, thrombin, recombinant melittin efficiently inhibits growth of the pathogenic bacterium Streptococcus pyogenes as effectively as melittin created by solid phase peptide synthesis. We conclude that a GST protein anchor can be used to immobilize functional protein to PEGDA microspheres and the protein will remain immobilized under physiological conditions until the protein is enzymatically released. PMID:23816641
Buhrman, Jason S; Cook, Laura C; Rayahin, Jamie E; Federle, Michael J; Gemeinhart, Richard A
Titanium and titanium alloys are key biomedical materials because of their good biocompatibility and mechanical properties. Nevertheless, infection on and around titanium implants still remains a problem which is usually difficult to treat and may lead to eventual implant removal. As a result, preventive measures are necessary to mitigate implant-frelated infection. One important strategy is to render the implant surface antibacterial by impeding the formation of a biofilm. A number of approaches have been proposed for this purpose and they are reviewed in this article. PMID:19637369
Zhao, Lingzhou; Chu, Paul K; Zhang, Yumei; Wu, Zhifen
This paper proposes an improved high throughput microbial method for the simultaneous performance of first and second level screening for antibacterial residues in meat. It is based on growth inhibition of B. subtilis on agar medium pH 6, 7.2 and 8, of B. cereus on agar medium pH 5.9, of M. luteus on agar medium pH 8 and of E. coli on agar medium pH 7.2 (research or first level screening) and on the use of confirmatory solutions (Pase, Paba, MgSO4) for the identification or second level screening. In kidney control samples, dialysis membranes were interposed between samples and the agar surface to both prevent the action of lysozyme and reduce false positive results. The proposed method detects beta-lactams, sulfonamides, tetracyclines, aminoglycosides, macrolides and quinolones at MRL concentrations and reliably indicates the inhibitor family. Results are obtained in 18-24 h. PMID:16393810
Ferrini, A M; Mannoni, V; Aureli, P
Binding to phospholipids, uptake by simple diffusion, and an energy-dependent, carrier-mediated efflux are thought to characterize interactions between fluoroquinolones and bacterial cytoplasmic membranes. Here, we have found that an endogenous active efflux is unlikely in quinolone-susceptible Staphylococcus aureus. The protonophore, carbonyl cyanide m-chlorophenylhydrazone (CCCP), increased pefloxacin uptake in different membrane systems under conditions which excluded carrier-mediated transport, i.e., in bacterial cells at 4 degrees C and in protein-free phosphatidylglycerol liposomes. When plotted as a function of outer pH, the CCCP effect, both in S. aureus cells and in phosphatidylglycerol liposomes, correlated with pefloxacin labeling of everted S. aureus membrane vesicles, with all three profiles showing maximal effect at an acidic pH. So the CCCP effect may result not from inhibition of the proton motive force, as previously thought, but rather from acidification of the intramembrane space by the protonophore, leading to enhanced binding of the positive pefloxacin species to the inner leaflet of the bilayer. Moreover, antistaphylococcal potency and uptake profiles of pefloxacin in S. aureus and phosphatidylglycerol liposomes, assayed as a function of outer pH, peaked at a neutral pH. These observations suggest that zwitterionic and positive quinolone species are responsible for diffusion through and binding to the cytoplasmic membrane, respectively.
Furet, Y X; Deshusses, J; Pechere, J C
The molecule 2-heptyl-3-hydroxy-4-quinolone (referred to as the Pseudomonas quinolone signal, or PQS) is produced by Pseudomonas aeruginosa as part of its quorum sensing circuit, and has been shown to influence a variety of processes in this bacterium, including the production of siderophores and secondary metabolites, virulence determinants and biofilm development. In this report we present evidence of the effect of PQS as an interspecies signal with a negative impact on the multicellular behaviour of Pseudomonas putida KT2440. PQS reduces biofilm formation and swarming motility, and interferes with iron uptake by this bacterium. Addition of PQS also causes changes in the transcription of several P. putida genes, indicating a specific response to the signal molecule, which is not produced by strain KT2440. Among the genes with increased expression in response to PQS is PP1563, which forms part of a large prophage cluster (PP1532-PP1584); consistently, phage-mediated lysis of some cells in the population was observed in the presence of PQS. Overall, these data indicate that PQS may be used by P. aeruginosa as a chemical weapon against potential competitors. PMID:21742029
Fernández-Pińar, Regina; Cámara, Miguel; Dubern, Jean-Frédéric; Ramos, Juan L; Espinosa-Urgel, Manuel
We carried out quantitative culturing of stools from 31 hospitalized alcoholic patients with cirrhosis and ascites, before treatment with 400 mg of norfloxacin per day, weekly for the first month, and then every 2 weeks thereafter for 15 to 229 days (median, 54 days). Members of the family Enterobacteriaceae virtually disappeared from the stools (< 10(2)/g), but treatment had little effect on enterococci. No selection of resistant organisms occurred in 15 patients, but the remaining 16 patients developed fecal organisms resistant to fluoroquinolones between days 14 and 43 of treatment (median, 25 days). Staphylococcus aureus was isolated four times, coagulase-negative Staphylococcus spp. were isolated six times, Citrobacter freundii was isolated four times, Enterobacter cloacae was isolated three times, Klebsiella oxytoca was isolated twice, Proteus rettgeri was isolated once, and untypeable streptococci were isolated six times. Some isolates persisted, while others were transient (one to seven consecutively positive cultures). The MICs of four quinolones (nalidixic acid, norfloxacin, ofloxacin, and ciprofloxacin) were determined by use of experimental microwell strips (ATB CMI; Biomerieux S.A.). All the strains isolated before treatment were susceptible to the four quinolones, with low MICs, whereas those isolated during norfloxacin treatment were highly resistant. Long-term norfloxacin administration thus carries a risk of disturbing the bacterial ecology in these patients, suggesting that digestive decontamination should no longer be prescribed routinely to cirrhotic patients with ascites.
Dupeyron, C; Mangeney, N; Sedrati, L; Campillo, B; Fouet, P; Leluan, G
Aminoglycosides are antibiotic drugs that act through binding to rRNA. In the search for antimicrobial amphiphilic aminoglycosides targeting bacterial membranes, we report here on the discovery of three dialkyl derivatives of the small aminoglycoside neamine active against susceptible and resistant Gram-positive and Gram-negative bacteria. One of these derivatives (R = 2-naphthylpropyl), which has good activity against MRSA and VRSA, showed a low toxicity in eukaryotic cells at 10 ?M. The synthesis of amphiphilic paromamine and neamine homologous derivatives pointed out the role of the 6'-amine function of the neamine core in the antibacterial effects. The optimal number of lipophilic substituents to be attached to the neamine core and the corresponding required lipophilicity determined here should permit a more selective targeting of bacterial membranes relative to eukaryotic membranes. This work revealed the existence of windows of lipophilicity necessary for obtaining strong antibacterial effects that should be of interest in the field of antibacterial amphiphilic aminoglycosides. PMID:24083676
Zimmermann, Louis; Bussičre, Antoine; Ouberai, Myriam; Baussanne, Isabelle; Jolivalt, Claude; Mingeot-Leclercq, Marie-Paule; Décout, Jean-Luc
A new lead class of antibacterial drug-like NAD synthetase (NADs) inhibitors was previously identified from a virtual screening study. Here a solution-phase synthetic library of 76 compounds, analogs of the urea-sulfonamide 5838, was synthesized in parallel to explore SAR on the sulfonamide aryl group. All library members were tested for enzyme inhibition against NADs and nicotinic acid mononucleotide adenylyltransferase (NaMNAT), the last two enzymes in the biosynthesis of NAD, and for growth inhibition in a B. anthracis antibacterial assay. Most compounds that inhibited bacterial growth also showed inhibition against one of the enzymes tested. While only modest enhancements in the enzyme inhibition potency against NADs were observed, of significance was the observation that the antibacterial urea-sulfonamides more consistently inhibited NaMNAT.
Moro, Whitney Beysselance; Yang, Zhengrong; Kane, Tasha A.; Zhou, Qingxian; Harville, Steve; Brouillette, Christie G.; Brouillette, Wayne J.
... test information in systemic antibacterial drug product labeling. Meeting Materials. FDA intends to make background material available to the public ... More results from www.fda.gov/advisorycommittees/calendar
The present study was carried out to evaluate the possible in vitro antibacterial potential of extracts of Eugenia jambolana seeds against multidrug-resistant human bacterial pathogens. Agar well diffusion and microbroth dilution assay methods were used for antibacterial susceptibility testing. Kill-kinetics study was done to know the rate and extent of bacterial killing. Phytochemical analysis and TLC-bioautography were performed by colour tests to characterize the putative compounds responsible for this antibacterial activity. Cytotoxic potential was evaluated on human erythrocytes by haemolytic assay method and acute oral toxicity study was done in mice. The plant extracts demonstrated varying degrees of strain specific antibacterial activity against all the test isolates. Further, ethyl acetate fraction obtained from fractionation of most active ethanol extract showed maximum antibacterial effect against all the test isolates. Phytochemical analysis and TLC-bioautography of ethyl acetate fraction revealed that phenolics were the major active phytoconstituents. Ethyl acetate fraction also demonstrated no haemolytic activity on human erythrocytes and no gross behavioural changes as well as toxic symptoms were observed in mice at recommended dosage level. The results provide justification for the use of E. jambolana in folk medicine to treat various infectious diseases and may contribute to the development of novel antimicrobial agents for the treatment of infections caused by these drug-resistant bacterial pathogens. PMID:22444436
Bag, Anwesa; Bhattacharyya, Subir Kumar; Pal, Nishith Kumar; Chattopadhyay, Rabi Ranjan
BACKGROUND: Predicting antibiotic resistance before it emerges at clinical settings constitutes a novel approach for preventing and fighting resistance of bacterial pathogens. To analyse the possibility that novel plasmid-encoded quinolone resistance determinants (Qnr) can emerge and disseminate among bacterial pathogens, we searched the presence of those elements in nearly 1000 bacterial genomes and metagenomes. RESULTS: We have found a number
María B Sánchez; Alvaro Hernández; José M Rodríguez-Martínez; Luis Martínez-Martínez; José L Martínez
Although quinolone resistance commonly results from chromosomal mutation, recent studies indicate that such resistance can also be transferred on plasmids carrying the gene responsible, qnr. One hundred ten ciprofloxacin-resistant clinical isolates of Klebsiella pneumoniae and Escherichia coli from the United States were screened for the qnr gene by PCR and Southern hybridization of plasmid DNA. Conjugation experiments were done with
Minggui Wang; Daniel F. Sahm; George A. Jacoby; David C. Hooper
There is increasing concern about the effects of pharmaceutical agents in the environment. The use of synthetic 4-quinolone compounds is rapidly increasing: newer and more complex analogues are being developed by the pharmaceutical industry to meet clinical and veterinary needs. This review aims at stimulating the need to consider the fate of pharmaceuticals in the environment as part of overall
Patrick K. Jjemba; Boakai K. Robertson
Chickens which had been experimentally-infected with a strain of Salmonella ententidis and treated by administration of enrofloxacin at commercially recommended concentrations in the drinking water, virtually eliminated this organism from the alimentary tract. However, an initially quinolone-sensitive Escherichia coli flora present in the birds' faeces was rapidly replaced by a quinolone-resistant flora which persisted after withdrawal of the medication. Resistance to quinolone in the form of nalidixic acid was transducible from a strain of S. typhimurium to S. enterinais with bacteriophage P22. PMID:18484047
Barrow, P A; Lovell, M A; Szmolleny, G; Murphy, C K
Two novel type III polyketide synthases, quinolone synthase (QNS) and acridone synthase (ACS), were cloned from Citrus microcarpa (Rutaceae). The deduced amino acid sequence of C. microcarpa QNS is unique, and it shared only 56-60% identities with C. microcarpa ACS, Medicago sativa chalcone synthase (CHS), and the previously reported Aegle marmelos QNS. In contrast to the quinolone- and acridone-producing A. marmelos QNS, C. microcarpa QNS produces 4-hydroxy-N-methylquinolone as the "single product" by the one-step condensation of N-methylanthraniloyl-CoA and malonyl-CoA. However, C. microcarpa ACS shows broad substrate specificities and produces not only acridone and quinolone but also chalcone, benzophenone, and phloroglucinol from 4-coumaroyl-CoA, benzoyl-CoA, and hexanoyl-CoA, respectively. Furthermore, the x-ray crystal structures of C. microcarpa QNS and ACS, solved at 2.47- and 2.35-? resolutions, respectively, revealed wide active site entrances in both enzymes. The wide active site entrances thus provide sufficient space to facilitate the binding of the bulky N-methylanthraniloyl-CoA within the catalytic centers. However, the active site cavity volume of C. microcarpa ACS (760 ?(3)) is almost as large as that of M. sativa CHS (750 ?(3)), and ACS produces acridone by employing an active site cavity and catalytic machinery similar to those of CHS. In contrast, the cavity of C. microcarpa QNS (290 ?(3)) is significantly smaller, which makes this enzyme produce the diketide quinolone. These results as well as mutagenesis analyses provided the first structural bases for the anthranilate-derived production of the quinolone and acridone alkaloid by type III polyketide synthases. PMID:23963450
Mori, Takahiro; Shimokawa, Yoshihiko; Matsui, Takashi; Kinjo, Keishi; Kato, Ryohei; Noguchi, Hiroshi; Sugio, Shigetoshi; Morita, Hiroyuki; Abe, Ikuro
Phenolic compounds, in general, exhibit antioxidant and antibacterial activities. We studied antimicrobial activity of the phenolic antioxidants, propofol (2,6-diisopropylphenol), tocopherol, eugenol, butylated hydroxyanisole (BHA), and several of their dimer compounds. Dipropofol (dimer of 2,6-diisopropylphenol) showed strong antibacterial activity against gram-positive strains including methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococci (VRE), while propofol and other monomeric and dimeric phenols having methyl or tert-butyl groups showed no remarkable activity. The results indicated that the dimeric structure of 2,6-diisopropylphenol moiety may play an important role in the antibacterial activity. PMID:15930760
Ogata, Masahiro; Tutumimoto Sato, Kanae; Kunikane, Takao; Oka, Kentaro; Seki, Masako; Urano, Shiro; Hiramatsu, Keiichi; Endo, Toyoshige
In this paper, novel multiaction antibacterial nanofibrous membranes containing apatite, Ag, AgBr and TiO2 as four active components were fabricated by an electrospinning technique. In this antibacterial membrane, each component serves a different function: the hydroxyapatite acts as the adsorption material for capturing bacteria, the Ag nanoparticles act as the release-active antibacterial agent, the AgBr nanoparticles act as the visible
Yiguang Wu; Weijie Jia; Qi An; Yuanfeng Liu; Jinchun Chen; Guangtao Li
Madurahydroxylactone (MHL), a secondary metabolite with antibacterial activity was evaluated for its suitability to generate controlled drug release coatings on medical implant materials. A smooth and firmly attached layer could be produced from a precursor solution on various metallic implant materials. In physiological salt solutions these coatings dissolved within a time period up to one week. A combination of MHL with a broad spectrum fluoroquinolone antibiotic was used to create a coating that was active against all bacterial strains tested. The time period during which the coating remained active against Pseudomonas aeruginosa was investigated. The results indicated a delayed drug release from single layer coatings in the course of seven days. MHL was biocompatible in cell culture assays and could after a delay even serve as a cell adhesion substrate for human or murine cells. The findings indicate a potential for MHL for the generation of delayed release antimicrobial implant coatings.
Badar, Muhammad; Hemmen, Katherina; Nimtz, Manfred; Stieve, Martin; Stiesch, Meike; Lenarz, Thomas; Hauser, Hansjorg; Mollmann, Ute; Vogt, Sebastian; Schnabelrauch, Matthias; Mueller, Peter P
Investigations on the 4-quinolone-3-carboxylic acid motif. 6. Synthesis and pharmacological evaluation of 7-substituted quinolone-3-carboxamide derivatives as high affinity ligands for cannabinoid receptors.
Within our studies on structure-activity relationships of 4-quinolone-3-carboxamides as cannabinoid ligands, a new series of compounds characterized by a fluoro or phenylthio group at 7-position and different substituents at N1 and carboxamide nitrogen were synthesized and evaluated for their binding ability to cannabinoid type 1 (CB1) and type 2 (CB2) receptors. Most of the compounds showed affinity for one or both cannabinoid receptors at nanomolar concentration, with K(i)(CB1) and K(i)(CB2) values ranging from 2.45 to >10,000 nM and from 0.09 to 957 nM, respectively. The N-(3,4-dichlorobenzyl)amide derivatives 27 and 40 displayed relatively low affinity, but high selectivity towards the CB1 receptor. Compounds 4 and 40, a CB2 and a CB1 ligand, respectively, behaved as partial agonists in the [(35)S]GTP?S assay. They showed very low permeability through (MDCK-MDR1) cells and might, therefore, represent possible lead structures for further optimization in the search for cannabinoid ligands unable to cross the blood-brain barrier. PMID:23085772
Pasquini, Serena; De Rosa, Maria; Ligresti, Alessia; Mugnaini, Claudia; Brizzi, Antonella; Caradonna, Nicola P; Cascio, Maria Grazia; Bolognini, Daniele; Pertwee, Roger G; Di Marzo, Vincenzo; Corelli, Federico
Since its discovery, qnrA has been found in most common Enterobacteriaceae. Ciprofloxacin MICs conferred by different qnrA-positive plasmids could range from 0.1 ?g/ml to 2 ?g/ml in Escherichia coli J53. The reasons for different ciprofloxacin MICs conferred by qnrA have not been fully clarified. Five hundred forty-one consecutive gram-negative clinical strains that were resistant or intermediate to ciprofloxacin and that were isolated in Shanghai in 2005 were screened for qnrA by PCR. For qnrA-positive isolates, the transferability of quinolone resistance was determined by conjugation and mutations within the quinolone resistance-determining region (QRDR) of gyrA and parC. aac(6?)-Ib-cr was detected and qnrA RNA expression was determined using real-time reverse transcription-PCR for transconjugants with different ciprofloxacin MICs. The qnrA gene was detected in 7 of the 541 clinical isolates. Quinolone resistance was transferred in four strains by conjugation. Mutations in the QRDR of gyrA and parC were detected in five qnrA-positive clinical strains with higher ciprofloxacin MICs. Of four qnrA-bearing plasmids in E. coli J53, pHS4 and pHS5 conferred ciprofloxacin MICs of 0.094 to 0.125 ?g/ml; pHS3, which harbored the aac(6?)-Ib-cr gene as well, conferred a ciprofloxacin MIC of 0.25 ?g/ml, and pHS6, which had both the aac(6?)-Ib-cr gene and a high expression level of qnrA, had a ciprofloxacin MIC of 1.0 ?g/ml. The prevalence of qnrA appeared to be higher in Enterobacter cloacae than in other Enterobacteriaceae. The coexistence of qnrA and aac(6?)-Ib-cr in a single plasmid and increased qnrA expression can account for the different levels of ciprofloxacin resistance seen in transconjugants.
Xu, Xiaogang; Wu, Shi; Ye, Xinyu; Liu, Yang; Shi, Wanliang; Zhang, Yingyuan; Wang, Minggui
Since its discovery, qnrA has been found in most common Enterobacteriaceae. Ciprofloxacin MICs conferred by different qnrA-positive plasmids could range from 0.1 microg/ml to 2 microg/ml in Escherichia coli J53. The reasons for different ciprofloxacin MICs conferred by qnrA have not been fully clarified. Five hundred forty-one consecutive gram-negative clinical strains that were resistant or intermediate to ciprofloxacin and that were isolated in Shanghai in 2005 were screened for qnrA by PCR. For qnrA-positive isolates, the transferability of quinolone resistance was determined by conjugation and mutations within the quinolone resistance-determining region (QRDR) of gyrA and parC. aac(6')-Ib-cr was detected and qnrA RNA expression was determined using real-time reverse transcription-PCR for transconjugants with different ciprofloxacin MICs. The qnrA gene was detected in 7 of the 541 clinical isolates. Quinolone resistance was transferred in four strains by conjugation. Mutations in the QRDR of gyrA and parC were detected in five qnrA-positive clinical strains with higher ciprofloxacin MICs. Of four qnrA-bearing plasmids in E. coli J53, pHS4 and pHS5 conferred ciprofloxacin MICs of 0.094 to 0.125 microg/ml; pHS3, which harbored the aac(6')-Ib-cr gene as well, conferred a ciprofloxacin MIC of 0.25 microg/ml, and pHS6, which had both the aac(6')-Ib-cr gene and a high expression level of qnrA, had a ciprofloxacin MIC of 1.0 microg/ml. The prevalence of qnrA appeared to be higher in Enterobacter cloacae than in other Enterobacteriaceae. The coexistence of qnrA and aac(6')-Ib-cr in a single plasmid and increased qnrA expression can account for the different levels of ciprofloxacin resistance seen in transconjugants. PMID:17724159
Xu, Xiaogang; Wu, Shi; Ye, Xinyu; Liu, Yang; Shi, Wanliang; Zhang, Yingyuan; Wang, Minggui
The continuing increase in the incidence of multi drug resistant pathogenic bacteria and shortage of new antimicrobial agents are the prime driver in efforts to identify the novel antimicrobial classes. In vitro antibacterial activity of 4-phenyl-1-(2-phenylallyl) pyridinium bromide was tested against Gram positive Staphylococcus aureus, Streptococcus species, Bacillus subtilis, and Gram negative Klebsiella aerogenes and Escherichia coli using disk diffusion method. Among them S. aureus showed strong antibacterial activity (21.99 ± 0.03 mm) while E. coli showed very little activity (8.97 ± 0.06 mm) towards the compound. The MIC of 4-phenyl-1-(2-phenyl-allyl)-pyridinium bromide for 90% S. aureus was ?20 ?g/ml and was compared with phenoxymethylpenicillin, cloxacillin, erythromycin and vancomycin. When 4-phenyl-1-(2-phenyl-allyl)pyridinium bromide showed MIC at ?20 ?g/ml, all others showed MIC at ?100 ?g/ml. Strong antibacterial activity of 4-phenyl-1-(2-phenyl-allyl)pyridinium bromide against S. aureus indicates that there is a possibility to use it as an effective antibacterial agent. PMID:23450086
Jayatissa, Rasanthika Nayomi; Perera, Rohan Prasantha; Hettiarachchi, Chamari Madhu; Weerawarna, Pathum Manjula
We studied the convulsant activity of sitafloxacin, a newly developed quinolone, and its interaction with anti-inflammatory drugs in mice. Intraventricular injections of sitafloxacin and levofloxacin induced convulsions dose-dependently in the mice. The value of the effective dose for producing convulsions in 50% of the mice (ED(50)) of sitafloxacin was 50.6 nmol/head, whereas that of levofloxacin was 76.7 nmol/head. The convulsant activity of these quinolones was not affected by concurrent administration with anti-inflammatory drugs. From these results obtained in a mouse model, it is suggested that sitafloxacin has weak convulsant activity and that the convulsant activity of sitafloxacin is not enhanced when it is administered with anti-inflammatory drugs. PMID:19688249
Although insects lack the basic entities of the vertebrate immune system, such as lymphocytes and immunoglobulins, they have developed alternative defence mechanisms against infections. Different types of peptide factors, exhibiting bactericidal activity, have been detected in some insect species. These humoral factors are induced upon infection. The present report describes the discovery of the apidaecins, isolated from lymph fluid of the honeybee (Apis mellifera). The apidaecins represent a new family of inducible peptide antibiotics with the following basic structure: GNNRP(V/I)YIPQPRPPHPR(L/I). These heat-stable, non-helical peptides are active against a wide range of plant-associated bacteria and some human pathogens, through a bacteriostatic rather than a lytic process. Chemically synthesized apidaecins display the same bactericidal activity as their natural counterparts. While only active antibacterial peptides are detectable in adult honeybee lymph, bee larvae contain considerable amounts of inactive precursor molecules.
Casteels, P; Ampe, C; Jacobs, F; Vaeck, M; Tempst, P
Despite considerable research and development efforts, the problem of infections related to biomedical devices and implants persists. Bacteria evidently can readily colonize surfaces of synthetic materials, such as those used for the fabrication of catheters, hip and knee implants, and many other devices. As the growing colony encapsulates itself with a protective exocellular bacterial polysaccharide layer, the biofilm becomes much harder to combat than circulating bacteria. Thus, there is a strong need to mitigate bacterial colonization by equipping the surfaces of biomedical devices and implants with features such as surface chemistry and surface roughness that are unfavorable for bacterial attachment. Here we review a number of strategies used for the design of antibacterial coatings. We also discuss specific issues that arise from using various types of coatings. PMID:19751126
Vasilev, Krasimir; Cook, Jessica; Griesser, Hans J
How to use bioactive peptide sequences as fundamental building blocks to make hydrogel materials which are stimuli-responsive? In this article, we provide a novel designed peptide comprising two antibacterial peptide sequences (KIGAKI)3-NH2 and a central tetrapeptide linker. Results show that balancing the forces of the electrostatic repulsion of the charged lysine residues against the hydrophobic collapse of the isoleucine and alanine residues and backbone ?-sheet hydrogen bonding allows the structural transition and formation of individually dispersed nanofibers. Circular Dichroism (CD) and rheology analysis demonstrated that the designed peptide can undergo an abrupt structural transition from a random coil to a stable unimolecular ?-hairpin conformation and subsequently form an elastic hydrogel when exposed to external stimuli such as pH, ionic strength and heat. The assembly kinetics of the obtained antibacterial sequence comprising peptide (ASCP) was studied by time-lapse Atomic Force Microscopy (AFM) and Thioflavin T (ThT) binding assay. In addition, the inherent antibacterial activity of the peptide hydrogel was confirmed by the antibacterial assay against Escherichia coli. This example described epitomizes the use of bioactive peptide sequences in the design of finite self-assembled structures with potential inherent activity. These hydrogel materials may find applications in drug delivery, tissue engineering and regenerative medicine.How to use bioactive peptide sequences as fundamental building blocks to make hydrogel materials which are stimuli-responsive? In this article, we provide a novel designed peptide comprising two antibacterial peptide sequences (KIGAKI)3-NH2 and a central tetrapeptide linker. Results show that balancing the forces of the electrostatic repulsion of the charged lysine residues against the hydrophobic collapse of the isoleucine and alanine residues and backbone ?-sheet hydrogen bonding allows the structural transition and formation of individually dispersed nanofibers. Circular Dichroism (CD) and rheology analysis demonstrated that the designed peptide can undergo an abrupt structural transition from a random coil to a stable unimolecular ?-hairpin conformation and subsequently form an elastic hydrogel when exposed to external stimuli such as pH, ionic strength and heat. The assembly kinetics of the obtained antibacterial sequence comprising peptide (ASCP) was studied by time-lapse Atomic Force Microscopy (AFM) and Thioflavin T (ThT) binding assay. In addition, the inherent antibacterial activity of the peptide hydrogel was confirmed by the antibacterial assay against Escherichia coli. This example described epitomizes the use of bioactive peptide sequences in the design of finite self-assembled structures with potential inherent activity. These hydrogel materials may find applications in drug delivery, tissue engineering and regenerative medicine. Electronic supplementary information (ESI) available: Fig. S1-S5. See DOI: 10.1039/c3nr00225j
Liu, Yanfei; Yang, Yanlian; Wang, Chen; Zhao, Xiaojun
Allyl isothiocyanate (AITC), a natural compound in plants belonging to the family Cruciferae, has been shown to have strong antimicrobial activity in liquid media as well as in its vapor form. To understand its antimicrobial mechanism, AITC was tested for bactericidal activities to Salmonella Montevideo, Escherichia coli O157:H7, and Listeria monocytogenes Scott A at different stages of growth and was compared with streptomycin, penicillin G, and polymyxin B, each of known antibacterial mechanisms. Bactericidal activities were determined by measuring bacterial viability and leakage of metabolites. To determine its effects on membrane permeability, beta-galactosidase activity was examined after exposure of E. coli K-12 strain 3.300 to the three antibiotics and to AITC. The two gram-negative bacteria, Salmonella Montevideo and E. coli O157:H7, were more sensitive to AITC and to polymyxin B than the gram-positive L. monocytogenes. AITC and polymyxin B were effective bactericidal agents to bacteria at all growth stages, whereas penicillin G and streptomycin did not exhibit bactericidal activity to stationary cells. High A260 and A280 values of cellular filtrate and beta-galactosidase activity were obtained after treatments of AITC and polymyxin B. These data indicated that AITC was most similar to polymyxin B with respect to its antibacterial effect on cell membranes and on leakage of cellular metabolites. Gaseous AITC caused metabolite leakages, measurable increases in 3-galactosidase activity, and reduction of viable bacteria. The effectiveness of AITC in inhibiting bacteria at all growth stages and its strong activity in vapor phase support its application in food preservation. PMID:10852565
Lin, C M; Preston, J F; Wei, C I
We report an 82-year-old man who developed ventricular tachycardia and Torsades de Pointes (TdP) after oral administration of garenoxacin, a novel quinolone antibiotic agent that differs from the third-generation quinolones, for pneumonia. He had hypokalemia (K 2.3 mmol/L) induced by licorice and also had received disopyramide for arrhythmia, bicalutamide for prostate cancer, and silodosin for prostate hypertrophy. After taking him off all drugs and administering spironolactone supplemented with potassium, his low serum potassium level was ameliorated. Therefore, although garenoxacin reportedly causes fewer adverse reactions for cardiac rhythms than third-generation quinolone antibiotics, one must be cautious of the interference of other drugs during hypokalemia in order to prevent TdP. PMID:19915794
Miyamoto, Kanyu; Kawai, Hirohisa; Aoyama, Ryuhei; Watanabe, Hitoshi; Suzuki, Keisuke; Suga, Norihiro; Kitagawa, Wataru; Miura, Naoto; Nishikawa, Kazuhiro; Imai, Hirokazu
Recently, understanding of how molecular modifications of the core quinolone structure affect(s) antimicrobial agent activity has progressed rapidly. Three positions (2, 3, and 4) cannot be changed without a significant loss of biological activity. Furthermore, it appears that a cyclopropyl group is optimal at position 1. Substituents at positions 5 and 8 affect planar configuration, and either a methyl or methoxy appear optimal at these sites. Hydrogen and amino groups have been investigated as useful substituents at position 6, replacing the fluorine of the fluoroquinolones. Interestingly, in vitro activity enhancement observed with alterations at positions 5 and 6 is not always accompanied by improved in vivo action. For all these modifications, the substituents at positions 7 and 8 are critical for potent antimicrobial activity. Optimizing overall molecular configuration enhances the number of intracellular targets for antimicrobial action (R-8) and impedes the efficiency of efflux proteins (R-7) that diminish intracellular penetration. PMID:11524717
Peterson, L R
The qnr genes are plasmid-borne fluoroquinolone-resistance determinants widespread in Enterobacteriaceae. Three families of qnr determinants (qnrA, B and S) have been described, but little is known about their expression and regulation. Two new determinants, qnrC and qnrD, have been found recently. Here, we describe the characterization of the qnrB2 promoter and the identification of a LexA-binding site in the promoter region of all qnrB alleles. LexA is the central regulator of the SOS response to DNA damage. We show that qnrB2 expression is regulated through the SOS response in a LexA/RecA-dependent manner, and that it can be induced by the quinolone ciprofloxacin, a known inducer of the SOS system. This is the first description of direct SOS-dependent regulation of an antibiotic-resistance mechanism in response to the antibiotic itself. PMID:19556999
Da Re, Sandra; Garnier, Fabien; Guérin, Emilie; Campoy, Susana; Denis, François; Ploy, Marie-Cécile
The qnr genes are plasmid-borne fluoroquinolone-resistance determinants widespread in Enterobacteriaceae. Three families of qnr determinants (qnrA, B and S) have been described, but little is known about their expression and regulation. Two new determinants, qnrC and qnrD, have been found recently. Here, we describe the characterization of the qnrB2 promoter and the identification of a LexA-binding site in the promoter region of all qnrB alleles. LexA is the central regulator of the SOS response to DNA damage. We show that qnrB2 expression is regulated through the SOS response in a LexA/RecA-dependent manner, and that it can be induced by the quinolone ciprofloxacin, a known inducer of the SOS system. This is the first description of direct SOS-dependent regulation of an antibiotic-resistance mechanism in response to the antibiotic itself.
Da Re, Sandra; Garnier, Fabien; Guerin, Emilie; Campoy, Susana; Denis, Francois; Ploy, Marie-Cecile
Inhibition of transfer of four conjugative R plasmids by ciprofloxacin, enoxacin, norfloxacin, ofloxacin, and pipemidic acid was investigated in an Escherichia coli mating system. The absolute concentrations needed for inhibition of conjugation varied from 0.12 microgram/ml for ciprofloxacin to 16 micrograms/ml for pipemidic acid, but the relationship to the MICs for the parent strains was identical for all substrates. Concentrations for a 90% reduction of transconjugants were in the range of one to six times the MIC for the parent strains, which also had lethal effects on donors and recipients. A similar effect on conjugation was found with chloramphenicol. These observations question the specificity of transfer inhibition by quinolones and cast doubt on the clinical importance of such an effect.
Weisser, J; Wiedemann, B
A series of 23 new 1-methyl-2-alkenyl-4(1H)quinolones have been synthesized and evaluated in vitro for their antimycobacterial activities against fast growing species of mycobacteria, such as Mycobacterium fortuitum, M. smegmatis and M. phlei. The compounds displayed good to excellent inhibition of the growth of the mycobacterial test strains with improved antimycobacterial activity compared to the hit compound, evocarpine. The most active compounds, which possessed chain length of 11–13 carbons at position-2 displayed potent inhibitory effects with an MIC value of 1.0 mg/L. In a human diploid embryonic lung cell line, MRC-5 cytotoxicity assay, the alkaloids showed weak to moderate cytotoxic activity. Biological evaluation of these evocarpine analogues on the less pathogenic fast growing strains of mycobacteria showed an interesting antimycobacterial profile and provided significant insight into the structure–activity relationships.
Wube, Abraham A.; Hufner, Antje; Thomaschitz, Christina; Blunder, Martina; Kollroser, Manfred; Bauer, Rudolf; Bucar, Franz
Quinolone-3-carboxylic acid represents a highly privileged chemotype in medicinal chemistry and has been extensively explored as antibiotics and antivirals targeting human immunodeficiency virus (HIV) integrase (IN). Herein we describe the synthesis and anti-hepatitis C virus (HCV) profile of a series of C-6 aryl substituted 4-quinlone-3-carboxylic acid analogues. Significant inhibition was observed with a few analogues at low micromolar range against HCV replicon in cell culture and a reduction in replicon RNA was confirmed through an RT-qPCR assay. Interestingly, evaluation of analogues as inhibitors of NS5B in a biochemical assay yielded only modest inhibitory activities, suggesting that a different mechanism of action could operate in cell culture. PMID:22748708
Chen, Yue-Lei; Zacharias, Jeana; Vince, Robert; Geraghty, Robert J; Wang, Zhengqiang
Aqueous extracts of ten medicinal plants were examined for their antibacterial potential against some reference strains of\\u000a human pathogenic bacteria. Anethum graveolens, Elettaria cardamomum, Foeniculum vulgare, Trachyspermum ammi and Viola odorata were found to be better\\/equally effective compared to standard antibiotics. V. odorata was the most effective antibacterial with minimum inhibitory concentration values ranging from 1 to 2%. The results
Daljit Singh Arora; Gurinder Jeet Kaur
The alternative sigma factor sigma54 has been implicated in diverse functions within the cells. In this study, we have constructed an rpoN mutant of Pseudomonas aeruginosa and investigated its importance as a target for antimicrobial agents, such as quinolones and carbapenems. The stationary-phase cells of the rpoN mutant displayed a survival rate approximately 15 times higher than that of the wild-type cells in the presence of quinolones and carbapenems. The stationary phase led to substantial production of pyoverdine by the P. aeruginosa rpoN mutant. Pyoverdine synthesis correlated with decreased susceptibility to antimicrobial agents. Quantitative real-time PCR revealed that stationary-phase cells of the rpoN mutant grown without an antimicrobial agent had approximately 4- to 140- and 2- to 14-fold-higher levels of transcripts of the pvdS and vqsR genes, respectively, than the wild-type strain. In the presence of an antimicrobial agent, levels of pvdS and vqsR transcripts were elevated 400- and 5-fold, respectively, in comparison to the wild-type levels. Flow cytometry assays using a green fluorescent protein reporter demonstrated increased expression of the vqsR gene in the rpoN mutant throughout growth. A pvdS mutant of P. aeruginosa, deficient in pyoverdine production, was shown to be susceptible to biapenem. These findings suggest that rpoN is involved in tolerance to antimicrobial agents in P. aeruginosa and that its tolerant effect is partly dependent on increased pyoverdine production and vqsR gene expression. PMID:17261620
Viducic, Darija; Ono, Tsuneko; Murakami, Keiji; Katakami, Mikiko; Susilowati, Heni; Miyake, Yoichiro
The alternative sigma factor ?54 has been implicated in diverse functions within the cells. In this study, we have constructed an rpoN mutant of Pseudomonas aeruginosa and investigated its importance as a target for antimicrobial agents, such as quinolones and carbapenems. The stationary-phase cells of the rpoN mutant displayed a survival rate approximately 15 times higher than that of the wild-type cells in the presence of quinolones and carbapenems. The stationary phase led to substantial production of pyoverdine by the P. aeruginosa rpoN mutant. Pyoverdine synthesis correlated with decreased susceptibility to antimicrobial agents. Quantitative real-time PCR revealed that stationary-phase cells of the rpoN mutant grown without an antimicrobial agent had approximately 4- to 140- and 2- to 14-fold-higher levels of transcripts of the pvdS and vqsR genes, respectively, than the wild-type strain. In the presence of an antimicrobial agent, levels of pvdS and vqsR transcripts were elevated 400- and 5-fold, respectively, in comparison to the wild-type levels. Flow cytometry assays using a green fluorescent protein reporter demonstrated increased expression of the vqsR gene in the rpoN mutant throughout growth. A pvdS mutant of P. aeruginosa, deficient in pyoverdine production, was shown to be susceptible to biapenem. These findings suggest that rpoN is involved in tolerance to antimicrobial agents in P. aeruginosa and that its tolerant effect is partly dependent on increased pyoverdine production and vqsR gene expression.
Viducic, Darija; Ono, Tsuneko; Murakami, Keiji; Katakami, Mikiko; Susilowati, Heni; Miyake, Yoichiro
We determined the nucleotide sequence of a 6-kb DNA region harboring the recF, orf192, gyrB, and gyrA genes from Mycobacterium smegmatis mc(2)155. The amino acid sequences deduced from gyrA and gyrB displayed 89 and 86% identity, respectively, with the DNA gyrase from Mycobacterium tuberculosis, and 67 and 65% identity, respectively, with that from Streptomyces coelicolor. An open reading frame encoding the C-terminal region of the M. smegmatis RecF polypeptide was found upstream from gyrB and was 57% identical to the open reading frame encoding the C-terminal region of the S. coelicolor RecF protein. The gene orf192 was identified between recF and gyrB and was 39% identical to orf191 found in S. coelicolor in the recF-gyrB region. The M. smegmatis DNA gyrase, which was purified by affinity chromatography on novobiocin-Sepharose, consisted of two polypeptides with apparent molecular masses of 98 and 80 kDa. Determination of the N-terminal amino acid sequence of the B subunit confirmed GTG as the start codon in gyrB. Analysis of the supercoiling activity of the enzyme indicated that the M. smegmatis DNA gyrase was characterized by a specific activity equivalent to that of the Escherichia coli DNA gyrase. Inhibition of this activity by 4-quinolones was investigated by determining the 50% inhibitory concentrations (IC50S) of nalidixic acid, ofloxacin, and ciprofloxacin. The results indicated that the inhibitory activities of these drugs against the M. smegmatis DNA gyrase were markedly lower than those previously reported for the E. coli DNA gyrase. The results also suggested that the higher levels of activity of ofloxacin and ciprofloxacin against M. smegmatis (MICs, 0.5 to 1 microgram/ml), in contrast to that of nalidixic acid (MIC, 256 micrograms/ml), could be related to the higher inhibitory activities of fluoroquinolones against the DNA gyrase from this species (IC50S, 7 to 14 micrograms/ml) compared with that of nalidixic acid (IC50, 1,400 micrograms/ml).
Revel-Viravau, V; Truong, Q C; Moreau, N; Jarlier, V; Sougakoff, W
DX-619 is a novel des-fluoro(6) quinolone with potent activity against gram-positive pathogens. The in vivo activity of DX-619 against Streptococcus pneumoniae was compared with those of fluoro(6) quinolones, sita- floxacin, and ciprofloxacin in a mouse model. Two strains of S. pneumoniae were used: a penicillin-sensitive S. pneumoniae (PSSP) strain and a penicillin-resistant S. pneumoniae (PRSP) strain. Furthermore, these strains showed
Yuichi Fukuda; Katsunori Yanagihara; Hideaki Ohno; Yasuhito Higashiyama; Yoshitsugu Miyazaki; Kazuhiro Tsukamoto; Yoichi Hirakata; Kazunori Tomono; Yohei Mizuta; Takayoshi Tashiro; Shigeru Kohno
Pyrano[3,2-c]pyridone and pyrano[3,2-c]quinolone structural motifs are commonly found in alkaloids manifesting diverse biological activities. As part of a program aimed at structural simplification of bioactive natural products utilizing multicomponent synthetic processes, we developed compound libraries based on these privileged heterocyclic scaffolds. The selected library members display low nanomolar antiproliferative activity and induce apoptosis in human cancer cell lines. Mechanistic studies reveal that these compounds induce cell cycle arrest in the G2/M phase and block in vitro tubulin polymerization. Because of the successful clinical use of microtubule-targeting agents, these heterocyclic libraries are expected to provide promising new leads in anticancer drug design.
Magedov, Igor V.; Manpadi, Madhuri; Ogasawara, Marcia A.; Dhawan, Adriana S.; Rogelj, Snezna; Van slambrouck, Severine; Steelant, Wim F. A.; Evdokimov, Nikolai M.; Uglinskii, Pavel Y.; Elias, Eerik M.; Knee, Erica J.; Tongwa, Paul; Antipin, Mikhail Yu.; Kornienko, Alexander
The influence of quinolones on electrically evoked pyramidal cell activity in the rat hippocampus in vitro was studied by using the slice technique. We hoped to learn more about the possible mechanisms for the development of side effects of different quinolones and to find a possible treatment. As reported earlier (W. Dimpfel, M. Spüler, A. Dalhoff, W. Hofmann, and G. Schlüter, Antimicrob. Agents Chemother. 35:1142-1146, 1991), the amplitude of the population spike increased in the presence of ciprofloxacin, lomefloxacin, or ofloxacin about twofold in comparison with reference values. This increase could be prevented in a concentration-dependent manner by the concomitant presence of 3-amino-1-hydroxy-2-pyrrolidone (HA 966), a compound acting at the so-called glycine site of the N-methyl-D-aspartate (NMDA) receptor, but not in the presence of aminophosphonovaleric acid (APV), which acts at a different recognition site of the NMDA receptor. Another tool, 6,7-dinitroquinoxaline-2,3-dione, an antagonist of the so-called AMPA receptor (named after the binding of L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] to this site), could not antagonize the effect induced by the quinolones. Activation of the glycine site of the NMDA receptor induced by the presence of D-serine in the superfusion medium also resulted in a concentration-dependent increase in the population spike amplitude. This response remained unchanged in the presence of ciprofloxacin, whereas lomefloxacin and ofloxacin led to further increases in the amplitude, especially in the presence of higher concentrations of D-serine. These results also point to an involvement of the glycine site of the central NMDA receptor in the development of side effects by different quinolones. A complete attenuation of the quinolone-induced effects was obtained in the presence of 2.5 microM gamma-hydroxybutyric acid (GHB), a physiological neuromodulator which is marketed in some countries of Europe as a sedative. It is therefore concluded that the excitatory adverse effects of quinolones might be treated by the administration of GHB.
Dimpfel, W; Dalhoff, A; von Keutz, E
The influence of quinolones on electrically evoked pyramidal cell activity in the rat hippocampus in vitro was studied by using the slice technique. We hoped to learn more about the possible mechanisms for the development of side effects of different quinolones and to find a possible treatment. As reported earlier (W. Dimpfel, M. Spüler, A. Dalhoff, W. Hofmann, and G. Schlüter, Antimicrob. Agents Chemother. 35:1142-1146, 1991), the amplitude of the population spike increased in the presence of ciprofloxacin, lomefloxacin, or ofloxacin about twofold in comparison with reference values. This increase could be prevented in a concentration-dependent manner by the concomitant presence of 3-amino-1-hydroxy-2-pyrrolidone (HA 966), a compound acting at the so-called glycine site of the N-methyl-D-aspartate (NMDA) receptor, but not in the presence of aminophosphonovaleric acid (APV), which acts at a different recognition site of the NMDA receptor. Another tool, 6,7-dinitroquinoxaline-2,3-dione, an antagonist of the so-called AMPA receptor (named after the binding of L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] to this site), could not antagonize the effect induced by the quinolones. Activation of the glycine site of the NMDA receptor induced by the presence of D-serine in the superfusion medium also resulted in a concentration-dependent increase in the population spike amplitude. This response remained unchanged in the presence of ciprofloxacin, whereas lomefloxacin and ofloxacin led to further increases in the amplitude, especially in the presence of higher concentrations of D-serine. These results also point to an involvement of the glycine site of the central NMDA receptor in the development of side effects by different quinolones. A complete attenuation of the quinolone-induced effects was obtained in the presence of 2.5 microM gamma-hydroxybutyric acid (GHB), a physiological neuromodulator which is marketed in some countries of Europe as a sedative. It is therefore concluded that the excitatory adverse effects of quinolones might be treated by the administration of GHB. PMID:8913467
Dimpfel, W; Dalhoff, A; von Keutz, E
In this paper, novel multiaction antibacterial nanofibrous membranes containing apatite, Ag, AgBr and TiO2 as four active components were fabricated by an electrospinning technique. In this antibacterial membrane, each component serves a different function: the hydroxyapatite acts as the adsorption material for capturing bacteria, the Ag nanoparticles act as the release-active antibacterial agent, the AgBr nanoparticles act as the visible sensitive and release-active antibacterial agent, and the TiO2 acts as the UV sensitive antibacterial material and substrate for other functional components. Using E. coli as the typical testing organism, such multicomponent membranes exhibit excellent antimicrobial activity under UV light, visible light or in a dark environment. The significant antibacterial properties may be due to the synergetic action of the four major functional components, and the unique porous structure and high surface area of the nanofibrous membrane. It takes only 20 min for the bacteria to be completely (99.9%) destroyed under visible light. Even in a dark environment, about 50 min is enough to kill all of the bacteria. Compared to the four component system in powder form reported previously, the addition of the electrospun membrane could significantly improve the antibacterial inactivation of E. coli under the same evaluation conditions. Besides the superior antimicrobial capability, the permanence of the antibacterial activity of the prepared free-standing membranes was also demonstrated in repeated applications.
Wu, Yiguang; Jia, Weijie; An, Qi; Liu, Yuanfeng; Chen, Jinchun; Li, Guangtao
Because of increase in bacterial resistance to common antibiotics, antibacterial nanometallopharmaceuticals have been drawing increasing interest. Recent literature reports encouraging results about the bactericidal activity of silver nanoparticles of either a simple or composite nature. We, for the first time, demonstrated that silver nanoparticles (AgNP) undergo a shape dependant interaction with bacteria. We also developed highly antibacterial porous carbon matrices
Joon Myong Song
To evaluate the possibility of an alternative to the traditional orthodontic stainless steel implants, the antibacterial activity against Porphyromonas gingivalis (P. gingivalis) and the related cytotoxicity of a type 304 Cu bearing antibacterial stainless steel were studied. The results indicated that the antibacterial stainless steel showed excellent antibacterial property against P. gingivalis, compared with the control steel (a purchased medical grade 304 stainless steel). Compared to the control steel, there were fewer bacteria on the surface of the antibacterial stainless steel, with significant difference in morphology. The cytotoxicities of the antibacterial stainless steel to both MG-63 and KB cells were all grade 1, the same as those of the control steel. There were no significant differences in the apoptosis rates on MG-63 and KB cells between the antibacterial stainless steel and the control steel. This study demonstrates that the antibacterial stainless steel is possible to reduce the incidence of implant-related infections and can be a more suitable material for the micro-implant than the conventional stainless steel in orthodontic treatment. PMID:23352947
Zhang, Dan; Ren, Ling; Zhang, Yang; Xue, Nan; Yang, Ke; Zhong, Ming
The development of drugs able to prevent and cure bacterial infections is one of the 20th century's major contributions to human longevity and quality of life. Antibacterial agents are among the most commonly prescribed drugs of any kind worldwide. Used appropriately, these drugs are lifesaving. To eliminate an infection as rapidly as possible, a sufficient concentration of the drug(s) chosen must reach the site of infection. Serum/tissue concentration is a result of various parameters such as absorption, excretion, protein binding and metabolic inactivation. Biliary excretion is an important route for the elimination of some drugs and drug metabolites in humans. Thus, drugs with a high bile concentration are indicated for the treatment of gallbladder infectious diseases. We present a review of a large number of antimicrobial agents most commonly used in daily clinical practice, with regard to their biliary excretion. PMID:12673103
Karachalios, George; Charalabopoulos, Konstantinos
Given the limited number of structural classes of clinically available antimicrobial drugs, the discovery of antibacterials with novel chemical scaffolds is an important strategy in the development of effective therapeu- tics for both naturally occurring and engineered resistant strains of pathogenic bacteria. In this study, several diarylamidine derivatives were evaluated for their ability to protect macrophages from cell death following
Rekha G. Panchal; Ricky L. Ulrich; Michelle M. Butler; Chad Houseweart; Timothy Opperman; John D. Williams; Norton P. Peet; Donald T. Moir; Tam Nguyen; Rick Gussio; Terry Bowlin; Sina Bavari
Rapid emergence of antibiotic-resistant bacterial pathogens limits the applicability of existing drugs, which has created an urgent need for novel antibiotics preferably with entirely new mechanisms of action. Oligodeoxynucleotides (ODNs) and their modified forms have been shown to inhibit bacterial gene expression, representing a potential for developing highly specific and efficacious antibacterial agents. In this study, a tetracycline (Tet)-inducible, randomized
Xin-Xing Tan; Yin Chen
2-(2?,4?-Dibromophenoxy)-4,6-dibromophenol isolated from the marine sponge Dysidea granulosa (Bergquist) collected off the coast of Lakshadweep islands, Indian Ocean, exhibited potent and broad spectrum in-vitro antibacterial activity, especially against methicillin resistant Staphylococcus aureus (MRSA), methicillin sensitive Staphylococcus aureus (MSSA), vancomycin resistant Enterococci (VRE), vancomycin sensitive Enterococci (VSE) and Bacillus spp. Minimal inhibitory concentration (MIC) was evaluated against 57 clinical and standard strains of Gram positive and Gram negative bacteria. The observed MIC range was 0.117–2.5 ?g/mL against all the Gram positive bacteria and 0.5–2 ?g/mL against Gram negative bacteria. The in-vitro antibacterial activity observed was better than that of the standard antibiotic linezolid, a marketed anti-MRSA drug. The results establish 2-(2?,4?-dibromophenoxy)-4,6-dibromophenol, as a potential lead molecule for anti-MRSA and anti-VRE drug development.
Shridhar, Divya M. P.; Mahajan, Girish B.; Kamat, Vijayendra P.; Naik, Chandrakant G.; Parab, Rajashri R.; Thakur, Nidhi R.; Mishra, Prabhu D.
Novel fluoroquinolone antibacterial agents containing oxime-substituted (aminomethyl)pyrrolidines: synthesis and antibacterial activity of 7-(4-(aminomethyl)-3-(methoxyimino)pyrrolidin-1-yl)-1-cyclopropyl-6- fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid (LB20304).
New pyrrolidine derivatives, which bear an alkyloxime substituent in the 4-position and an aminomethyl substituent in the 3-position of the pyrrolidine ring, have been synthesized and coupled with various quinolinecarboxylic acids to produce a series of new fluoroquinolone antibacterials. These fluoroquinolones were found to possess potent antimicrobial activity against both Gram-negative and Gram-positive organisms, including methicillin resistant Staphylococcus aureus (MRSA). Variations at the C-8 position of the quinolone nucleus included fluorine, chlorine, nitrogen, methoxy, and hydrogen atom substitution. The activity imparted to the substituted quinolone nucleus by the C-8 substituent was in the order F (C5-NH2) > F (C5-H) > naphthyridine > Cl = OMe = H against Gram-positive organisms. In the case of Gram-negative strains, activity was in the order F (C5-NH2) > naphthyridine = F (C5-H) > H > Cl > OMe. The advantages provided by the newly introduced oxime group of the quinolones were clearly demonstrated by their comparison to a desoximino compound 30. In addition, the oxime moiety greatly improved the pharmacokinetic parameters of the novel quinolones. Among these compounds, compound 20 (LB20304) showed the best in vivo efficacy and pharmacokinetic profile in animals, as well as good physical properties. The MICs (microgram/mL) of LB20304, compound 30, and ciprofloxacin against several test organisms are as follows: S. aureus 6538p (0.008, 0.031, and 0.13), methicillin resistant S. aureus 241 (4, 16, and 128), Streptococcus epidermidis 887E (0.008, 0.016, and 0.13), methicillin resistant S. epidermidis 178 (4, 32, and 128), Enterococcus faecalis 29212 (0.063, 0.13, and 1), Pseudomonas aeruginosa 1912E (0.25, 0.5, and 0.13), Escherichia coli 3190Y (0.008, 0.016, and 0.008), Enterobacter cloacae P99 (0.008, 0.031, and 0.008), Actinobacter calcoaceticus 15473 (0.063, 0.13, and 0.25). On the basis of these promising results, LB20304 was selected as a candidate for further evaluation. PMID:9357525
Hong, C Y; Kim, Y K; Chang, J H; Kim, S H; Choi, H; Nam, D H; Kim, Y Z; Kwak, J H
The in vitro activity of pefloxacin, a new fluoroquinolone, was compared with that of 5 other quinolone compounds (nalidixic and pipemidic acids, norfloxacin, ciprofloxacin, and ofloxacin) against 416 strains of Proteae spp. isolated from urine specimens of hospitalized patients with acute urinary tract infections (UTI). Ciprofloxacin was the most active agent. Norfloxacin, ofloxacin, and pefloxacin were similarly active against Proteus strains (MIC90 = 0.39 microgram/ml). Against Providencia spp. pefloxacin and norfloxacin showed similar activity (MIC90 = 3.12 micrograms/ml). There is minimal discrepancy between minimum inhibitory concentrations and minimum bactericidal concentrations exhibited by the quinolones for all urinary tract pathogens tested. Our in vitro studies indicate that pefloxacin is an active antimicrobial agent and suggest that it will prove useful in the treatment of complicated urinary tract infections due to nalidixic acid-resistant Proteae spp. PMID:3224396
Piccolomini, R; Cellini, L; Allocati, N; Di Girolamo, A; Selan, L; Scazzocchio, F
Antibiotic-resistant bacteria are an increasing source of concern in all environments in which these drugs have been used.\\u000a More stringent regulations have led to a slow but sure decrease in antibiotic use in the food industry worldwide, but have\\u000a also stimulated the search for alternative antibacterial agents. In medicine, the number of people infected with pan-resistant\\u000a bacteria is driving research
Damien Maura; Laurent Debarbieux
Summary The majority of deaths in severe pancreatitis are the result of superinfection of necrotic tissue. The pathogen most commonly\\u000a responsible for such infections isEscherichia coli. Antibiotic prophylaxis would appear a logical precaution. The antibacterial drugs of choice should possess two basic characteristics:\\u000a they must be active against the flora responsible for the infections and must be capable of penetrating into
Claudio Bassi; Roberta Fontana; Sergio Vesentini; Giorgio Cavallini; Luigi Marchiori; Massimo Falconi; Stefano Corra; Paolo Pederzoli
From July to December 2006, a panel of 401 enterococci was isolated from carcass rinse samples collected in five poultry processing\\u000a plants in New Zealand. Agar diffusion assays for nine antibacterial drugs were used to obtain a resistance phenotype for each\\u000a isolate. Hierarchical clustering techniques and diversity indices showed a high diversity of resistance phenotypes within\\u000a each plant, with populations
Eve Pleydell; Lynn Rogers; Errol Kwan; Nigel French
Natural dyes find use in the coloring of textiles, drugs, cosmetics, etc. Owing to their nontoxic effects, they are also used\\u000a for coloring various food products. In the present study antimicrobial properties of 8 food dyes against 10 bacteria and 5\\u000a fungal organisms were investigated. It was observed that red dyes showed best antibacterial activity while yellow dyes showed\\u000a better
Ramamoorthy Siva; Meera George Palackan; Lubaina Maimoon; T. Geetha; Dipita Bhakta; P. Balamurugan; S. Rajanarayanan
A total of 225 isolates of Salmonella enterica serovar Typhimurium from food-producing animals collected between 2003 and 2007 were examined for the prevalence of plasmid-mediated quinolone resistance (PMQR) determinants, namely qnrA, qnrB, qnrC, qnrD, qnrS, qepA and aac(6')Ib-cr, in Japan. Two isolates (0.8%) of S. Typhimurium DT104 from different dairy cows on a single farm in 2006 and 2007 were
Tetsuo Asai; Chizuru Sato; Kaori Masani; Masaru Usui; Manao Ozawa; Tomoe Ogino; Hiroshi Aoki; Takuo Sawada; Hidemasa Izumiya; Haruo Watanabe
We evaluated the pharmacokinetic\\/pharmacodynamic parameters of 8 oral quinolones (ciprofloxacin, garenoxacin [GRNX], gatifloxacin, levofloxacin, moxifloxacin, prulifloxacin, sitafloxacin, and sparfloxacin) on 11 fluoroquinolone-resistant Streptococcus pneumoniae strains, screened from 780 strains isolated from various clinical sources in Japan. GRNX showed the highest area under the blood concentration time curve\\/MIC ratios, which exceeded the target values for bacterial eradication against all fluoroquinolone-resistant S.
Shin-ichi Yokota; Yasuo Ohkoshi; Nobuhiro Fujii
We evaluated the pharmacokinetic/pharmacodynamic parameters of 8 oral quinolones (ciprofloxacin, garenoxacin [GRNX], gatifloxacin, levofloxacin, moxifloxacin, prulifloxacin, sitafloxacin, and sparfloxacin) on 11 fluoroquinolone-resistant Streptococcus pneumoniae strains, screened from 780 strains isolated from various clinical sources in Japan. GRNX showed the highest area under the blood concentration time curve/MIC ratios, which exceeded the target values for bacterial eradication against all fluoroquinolone-resistant S. pneumoniae strains. PMID:19679241
Yokota, Shin-ichi; Ohkoshi, Yasuo; Fujii, Nobuhiro
Extended-spectrum ?-lactamase (ESBL)-producing bacteria are known to be resistant to penicillins, cephalosporins, and monobactams\\u000a because of their substrate specificity, and these bacteria are sensitive only to a narrow range of antimicrobial agents. The\\u000a 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
Tatsuya Nakamura; Chihiro Shimizu; Mayumi Kasahara; Kazuyuki Okuda; Chiyo Nakata; Hiroko Fujimoto; Hiroe Okura; Masaru Komatsu; Kouichi Shimakawa; Noriyuki Sueyoshi; Toshiro Ura; Kaori Satoh; Masahiro Toyokawa; Yasunao Wada; Tamaki Orita; Tomomi Kofuku; Katsutoshi Yamasaki; Masako Sakamoto; Hisaaki Nishio; Shohiro Kinoshita; Hakuo Takahashi
The purpose of this study was to evaluate the prevalence and clinical risk factors for quinolone resistance (QR) in E. coli strains from males with febrile urinary tract infection (FUTI). An ambispective cross-sectional study was performed in which\\u000a we evaluated 153 males with a community FUTI caused by E. coli. Among the 153 FUTI episodes, 101 (66%) were due to
A. Smithson; C. Chico; J. Ramos; C. Netto; M. Sanchez; J. Ruiz; R. Porron; M. T. Bastida
Novel non-fluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. N-Linked amino piperidines, such as 7a, generally show potent antibacterial activity, including against quinolone-resistant isolates, but suffer from hERG inhibition (IC(50) = 44 ?M for 7a) and QT prolongation in vivo. We now disclose the finding that new analogues of 7a with reduced pK(a) due to substitution with an electron-withdrawing substituent in the piperidine moiety, such as R,S-7c, retained the Gram-positive activity of 7a but showed significantly less hERG inhibition (IC(50) = 233 ?M for R,S-7c). This compound exhibited moderate clearance in dog, promising efficacy against a MRSA strain in a mouse infection model, and an improved in vivo QT profile as measured in a guinea pig in vivo model. As a result of its promising activity, R,S-7c was advanced into phase I clinical studies. PMID:22779424
Reck, Folkert; Alm, Richard A; Brassil, Patrick; Newman, Joseph V; Ciaccio, Paul; McNulty, John; Barthlow, Herbert; Goteti, Kosalaram; Breen, John; Comita-Prevoir, Janelle; Cronin, Mark; Ehmann, David E; Geng, Bolin; Godfrey, Andrew Aydon; Fisher, Stewart L
A novel furanone-containing antibacterial resin composite has been prepared and evaluated. compressive strength (CS) and Streptococcus mutans viability were used to evaluate the mechanical strength and antibacterial activity of the composites. The modified resin composites showed a significant antibacterial activity without substantially decreasing the mechanical strengths. With 5-30 % addition of the furanone derivative, the composite kept its original CS unchanged but showed a significant antibacterial activity with a 16-68 % reduction in the S. mutans viability. Further, the antibacterial function of the new composite was not affected by human saliva. The aging study indicates that the composite may have a long-lasting antibacterial function. Within the limitations of this study, it appears that the experimental antibacterial resin composite may potentially be developed into a clinically attractive dental restorative due to its high mechanical strength and antibacterial function. PMID:22466818
Weng, Yiming; Howard, Leah; Guo, Xia; Chong, Voon Joe; Gregory, Richard L; Xie, Dong
Nine coordination compounds of Cu(II) and Co(II) with Ciprofloxacin (HCp) and Enoxacin (HEx) as ligands have been prepared and characterized. Single crystal structural determinations of [Cu(HCp)2(ClO4)2]·6H2O (1) and [Co(HEx)2(Ex)]Cl·2CH3OH·12H2O (4) are reported. The crystal of 1 is composed of [Cu(HCp)2(ClO4)2] units with the two perchlorate anions semicoordinated, and uncoordinated water molecules. The copper ion, at a crystallographic inversion centre, is
N. Jiménez-Garrido; L. Perelló; R. Ortiz; G. Alzuet; M. González-Álvarez; E. Cantón; M. Liu-González; S. García-Granda; M. Pérez-Priede
A search for antibacterial activity in different body-parts of Pandalus borealis (northern shrimp), Pagurus bernhardus (hermit crab), Hyas araneus (spider crab) and Paralithodes camtschatica (king crab) was conducted. Dried samples were extracted with 60% (v/v) acetonitrile, containing 0.1% (v/v) trifluoroacetic acid, and further extracted and concentrated on C18 cartridges. Eluates from the solid phase extraction were tested for antibacterial, lysozyme and haemolytic activity. Antibacterial activity against Escherichia coli, Vibrio anguillarum, Corynebacterium glutamicum and Staphylococcus aureus was detected in extracts from several tissues in all species tested, but mainly in the haemolymph and haemocyte extracts. V. anguillarum and C. glutamicum were generally the most sensitive micro-organisms. In P. borealis and P. bernhardus most of the active fractions were not affected by proteinase K treatment, while in H. araneus and P. camtschatica most fractions were sensitive to proteinase K treatment, indicating antibacterial factors of proteinaceous nature. In P. bernhardus the active fractions were generally heat labile, whereas in H. araneus the activities were resistant to heat. Differences between active extracts regarding hydrophobicity and sensitivity for heat and proteinase K treatment indicate that several compounds are responsible for the antibacterial activities detected. Lysozyme-like activity could be detected in some fractions and haemolytic activity against human red blood cells could be detected in haemolymph/haemocyte and exoskeleton extracts from all species tested. PMID:12194450
Haug, Tor; Kjuul, Anita K; Stensvĺg, Klara; Sandsdalen, Erling; Styrvold, Olaf B
Isothiazoloquinolones containing functionalized aromatic hydrocarbons at the 7-position: synthesis and in vitro activity of a series of potent antibacterial agents with diminished cytotoxicity in human cells.
This report describes 9H-isothiazolo[5,4-b]quinoline-3,4-diones (ITQs) containing aromatic groups at the 7-position that were prepared using palladium-catalyzed cross-coupling and tested against a panel of susceptible and resistant bacteria. In general, these compounds were more effective against Gram-positive than Gram-negative organisms. Many of the ITQs were more potent than contemporary quinolones and displayed a particularly strong antistaphylococcal activity against a clinically important, multi-drug-resistant strain. In contrast with ITQs reported previously, several of the analogues described in this Letter demonstrated low cytotoxic activity against a human cell line. PMID:16337791
Wiles, Jason A; Wang, Qiuping; Lucien, Edlaine; Hashimoto, Akihiro; Song, Yongsheng; Cheng, Jijun; Marlor, Christopher W; Ou, Yangsi; Podos, Steven D; Thanassi, Jane A; Thoma, Christy L; Deshpande, Milind; Pucci, Michael J; Bradbury, Barton J
Pseudomonas aeruginosa is well-recognized as a nosocomial pathogen, which exhibits inherent drug resistance. In this study, the antibacterial activity of ethanol extracts of 58 Chinese herbal medicines used in Taiwan were tested against 89 nosocomial antibiotic resistant strains of Pseudomonas aeruginosa. The results gathered by the disc diffusion method showed that 26 out of the 58 herbal extracts exhibited antibacterial activity. Among the 26 herbal extracts, 10 extracts showed broad-spectrum antibacterial activities and were selected for further antibacterial property assay. The minimum inhibitory concentrations (MIC) of the active partition fractions ranged from 0.25 to 11.0 mg/L. The presence of flavonoid compounds in the active fractions of test herbal extracts was observed by the TLC-bioautography. The results from the time-kill assay revealed that most of the herbal extracts completely killed the test organisms within 4 hours. Exposure of the test strains to a sub-MIC level of the herbal extracts for 10 consecutive subcultures did not induce resistance to the active components. A combination of the active herbal fractions with antibiotics showed that one of the herbal medicines, the hexane fraction of Ramulus Cinnamomi, possessed a synergistic effect with tetracycline, gentamycin, and streptomycin. In conclusion, the tested Chinese medical herbs have the potential to be developed into natural antibiotics. This is the first evaluation for screening large amounts of medical plants against nosocomial antibiotic resistant bacteria in Taiwan. PMID:18186590
Liu, Ching-Shen; Cham, Thau-Ming; Yang, Cheng-Hong; Chang, Hsueh-Wei; Chen, Chia-Hong; Chuang, Li-Yeh
Objective To access the in vitro antibacterial activity of Hibiscus rosa-sinensis (H. rosa- sinensis) flower extract against human pathogens. Methods Antibacterial activity was evaluated by using disc and agar diffusion methods. The protein was run through poly acrylmide gel electrophoresis to view their protein profile. Results The results showed that the cold extraction illustrates a maximum zone of inhibition against Bacillus subtillis (B. subtillis), Escherichia coli (E. coli) viz., (17.00 ± 2.91), (14.50 ± 1.71) mm, followed by hot extraction against, E. coli, Salmonella sp. as (11.66 ± 3.14), (10.60 ± 3.09) mm. In methanol extraction showed a highest zone of inhibition recorded against B. subtillis, E. coli as (18.86 ± 0.18), (18.00 ± 1.63) mm pursued by ethanol extraction showed utmost zone of inhibition recorded against Salmonella sp. at (20.40 ± 1.54) mm. The crude protein from flower showed a maximum inhibitory zone observed against Salmonella sp., E. coli viz., (16.55 ± 1.16), (14.30 ± 2.86) mm. The flower material can be taken as an alternative source of antibacterial agent against the human pathogens. Conclusions The extracts of the H. rosa-sinensis are proved to have potential antibacterial activity, further studies are highly need for the drug development.
Ruban, P; Gajalakshmi, K
How to use bioactive peptide sequences as fundamental building blocks to make hydrogel materials which are stimuli-responsive? In this article, we provide a novel designed peptide comprising two antibacterial peptide sequences (KIGAKI)3-NH2 and a central tetrapeptide linker. Results show that balancing the forces of the electrostatic repulsion of the charged lysine residues against the hydrophobic collapse of the isoleucine and alanine residues and backbone ?-sheet hydrogen bonding allows the structural transition and formation of individually dispersed nanofibers. Circular Dichroism (CD) and rheology analysis demonstrated that the designed peptide can undergo an abrupt structural transition from a random coil to a stable unimolecular ?-hairpin conformation and subsequently form an elastic hydrogel when exposed to external stimuli such as pH, ionic strength and heat. The assembly kinetics of the obtained antibacterial sequence comprising peptide (ASCP) was studied by time-lapse Atomic Force Microscopy (AFM) and Thioflavin T (ThT) binding assay. In addition, the inherent antibacterial activity of the peptide hydrogel was confirmed by the antibacterial assay against Escherichia coli. This example described epitomizes the use of bioactive peptide sequences in the design of finite self-assembled structures with potential inherent activity. These hydrogel materials may find applications in drug delivery, tissue engineering and regenerative medicine. PMID:23739953
Liu, Yanfei; Yang, Yanlian; Wang, Chen; Zhao, Xiaojun
Synthesis and antibacterial activity of metronidazole–triazole conjugates are reported. Total 21 hybrid compounds have been synthesized with different substitution pattern on the triazole ring in order to study their influence on the antibacterial activity. These compounds demonstrated potent to weak antibacterial activity against Gram-positive, and Gram-negative bacteria. Six compounds have shown equal or better antibacterial activity against Gram-negative strains than
Beena; Nitin Kumar; Rajesh K. Rohilla; N. Roy; Diwan S. Rawat
A microbial isolate, characterized as Streptomyces sp. (MTCC 6819), produced antifungal metabolite intracellularly and antibacterial metabolite extracellularly under submerged\\u000a fermentation conditions. This Gram-positive bacterium showed broad antimicrobial activity spectra against both Gram-positive\\u000a and Gram-negative bacteria. The minimum inhibitory concentration (MIC) of partially purified (68.4%) antibacterial metabolite\\u000a ranged between 50 and 12.5 ?g\\/mL against multiple-drug-resistant bacteria. The producer organism exhibited strong
Jaspreet Banga; Vandana Praveen; Vineeta Singh; C. K. M. Tripathi; Vinod Bihari
Although plant polyphenols such as (?)-epigallocatechin gallate (EGCG) have antibacterial activity towards methicillin-resistant Staphylococcus aureus (MRSA), such polyphenols are unstable in solution. Because the instability of polyphenols is attributable to their oxidation, we examined the effects of antioxidants and inhibitors of polyphenol oxidation on the maintenance of polyphenol antibacterial activity. The antibacterial activity of EGCG was enhanced in the presence
Tsutomu Hatano; Mayumi Tsugawa; Miwako Kusuda; Shoko Taniguchi; Takashi Yoshida; Sumiko Shiota; Tomofusa Tsuchiya
Nutmeg (Myristica fragrans) is used in food preparations for its aromatic flavor. The present investigation was undertaken to evaluate the antibacterial activity of constituents of M. fragrans seeds. Seeds of M. fragrans were powdered and extracted with chloroform to obtain trimyristin, which on saponification yielded myristic acid. The mother liquor remaining after separation of trimyristin was concentrated and column-chromatographed with petroleum ether to separate myristicin. Antibacterial activity of these isolated constituents was evaluated by determination of minimum inhibitory concentration against selected Gram-positive and Gram-negative organisms. All the constituents isolated from nutmeg exhibited good antibacterial activity. This study shows the potential of natural compounds in replacement of synthetic preservatives. PMID:17004905
Narasimhan, Balasubramanian; Dhake, Avinash S
The antifungal and antibacterial properties of a series of 70 diarylamidine derivatives were evaluated. Several of these compounds exhibited considerable antimicrobial potency. A survey of the structure-activity relationship demonstrated that minor structural variations resulted in significant changes of antimicrobial activity. In general, the structural features required for antifungal activity coincided with those required for antibacterial activity. Both the antifungal and the antibacterial properties of the diarylamidines depended on the presence and the positions, of both amidino groups, on the nature of the central bridge connecting the two aryl moieties, and on the nature of these aryl residues (preferably indole). The most active compound was evaluated for its activity against Candida albicans infection in mice.
Anne, J; De Clercq, E; Eyssen, H; Dann, O
We studied the convulsant activity of sitafloxacin, a newly developed quinolone, and its interaction with anti-inflammatory\\u000a drugs in mice. Intraventricular injections of sitafloxacin and levofloxacin induced convulsions dose-dependently in the mice.\\u000a The value of the effective dose for producing convulsions in 50% of the mice (ED50) of sitafloxacin was 50.6 nmol\\/head, whereas that of levofloxacin was 76.7 nmol\\/head. The convulsant
Actinopyga lecanora, a type of sea cucumber commonly known as stone fish with relatively high protein content, was explored as raw material for bioactive peptides production. Six proteolytic enzymes, namely alcalase, papain, pepsin, trypsin, bromelain and flavourzyme were used to hydrolyze A. lecanora at different times and their respective degrees of hydrolysis (DH) were calculated. Subsequently, antibacterial activity of the A. lecanora hydrolysates, against some common pathogenic Gram positive bacteria (Bacillus subtilis and Staphylococcus aureus) and Gram negative bacteria (Escherichia coli, Pseudomonas aeruginosa, and Pseudomonas sp.) were evaluated. Papain hydrolysis showed the highest DH value (89.44%), followed by alcalase hydrolysis (83.35%). Bromelain hydrolysate after one and seven hours of hydrolysis exhibited the highest antibacterial activities against Pseudomonas sp., P. aeruginosa and E. coli at 51.85%, 30.07% and 30.45%, respectively compared to the other hydrolysates. Protein hydrolysate generated by papain after 8 h hydrolysis showed maximum antibacterial activity against S. aureus at 20.19%. The potent hydrolysates were further fractionated using RP-HPLC and antibacterial activity of the collected fractions from each hydrolysate were evaluated, wherein among them only three fractions from the bromelain hydrolysates exhibited inhibitory activities against Pseudomonas sp., P. aeruginosa and E. coli at 24%, 25.5% and 27.1%, respectively and one fraction of papain hydrolysate showed antibacterial activity of 33.1% against S. aureus. The evaluation of the relationship between DH and antibacterial activities of papain and bromelain hydrolysates revealed a meaningful correlation of four and six order functions. PMID:23222684
Ghanbari, Raheleh; Ebrahimpour, Afshin; Abdul-Hamid, Azizah; Ismail, Amin; Saari, Nazamid
Actinopyga lecanora, a type of sea cucumber commonly known as stone fish with relatively high protein content, was explored as raw material for bioactive peptides production. Six proteolytic enzymes, namely alcalase, papain, pepsin, trypsin, bromelain and flavourzyme were used to hydrolyze A. lecanora at different times and their respective degrees of hydrolysis (DH) were calculated. Subsequently, antibacterial activity of the A. lecanora hydrolysates, against some common pathogenic Gram positive bacteria (Bacillus subtilis and Staphylococcus aureus) and Gram negative bacteria (Escherichia coli, Pseudomonas aeruginosa, and Pseudomonas sp.) were evaluated. Papain hydrolysis showed the highest DH value (89.44%), followed by alcalase hydrolysis (83.35%). Bromelain hydrolysate after one and seven hours of hydrolysis exhibited the highest antibacterial activities against Pseudomonas sp., P. aeruginosa and E. coli at 51.85%, 30.07% and 30.45%, respectively compared to the other hydrolysates. Protein hydrolysate generated by papain after 8 h hydrolysis showed maximum antibacterial activity against S. aureus at 20.19%. The potent hydrolysates were further fractionated using RP-HPLC and antibacterial activity of the collected fractions from each hydrolysate were evaluated, wherein among them only three fractions from the bromelain hydrolysates exhibited inhibitory activities against Pseudomonas sp., P. aeruginosa and E. coli at 24%, 25.5% and 27.1%, respectively and one fraction of papain hydrolysate showed antibacterial activity of 33.1% against S. aureus. The evaluation of the relationship between DH and antibacterial activities of papain and bromelain hydrolysates revealed a meaningful correlation of four and six order functions.
Ghanbari, Raheleh; Ebrahimpour, Afshin; Abdul-Hamid, Azizah; Ismail, Amin; Saari, Nazamid
Salmonella enterica serovar Enteritidis is a well-known pathogenic bacterium responsible for human gastrointestinal enteritis mainly due to the consumption of eggs and egg-products. The first aim of this work was to study several virulence factors of a strain isolated from egg content: SEovo. First, bacterial growth was studied at several temperatures and cell morphology was observed by scanning electronic microscopy. These experiments showed Salmonella's ability to grow at low temperatures and to produce exoproducts. Next, Salmonella motility was observed performing swimming, twitching, and swarming tests. Results indicated a positive flagellar activity and the cell ability to differentiate and become hyperflagellated under specific conditions. Moreover, SEovo adherence and biofilm formation was carried out. All of these tests enabled us to conclude that SEovo is a potential pathogen, thus it can be used as a model to perform antibacterial experiments. The second part of the study was dedicated to the evaluation of the antibacterial activity of different molecules using several methods. The antibacterial effect of silver and copper aluminosilicates was tested by two different kinds of methods. On the one hand, the effect of these two antibacterial agents was determined using microbiological methods: viable cell count and agar-well diffusion. And on the other hand, the antibacterial activity was evaluated using CLSM and SYTO Red/SYTOX Green dyeing. CLSM allowed for the evaluation of the biocide on sessile cells, whereas the first methods did not. Results showed that adhered bacteria were more resistant than planktonic counterparts and that CLSM was a good alternative to evaluate antibacterial activity on fixed bacteria without having to carry out a removing step. PMID:21717317
Legendre, Gaëlle; Fa˙, Fabienne; Linossier, Isabelle; Vallée-Réhel, Karine
Bacteriophages have been used for more than a century for (unconventional) therapy of bacterial infections, for half a century as tools in genetic research, for 2 decades as tools for discovery of specific target-binding proteins, and for nearly a decade as tools for vaccination or as gene delivery vehicles. Here we present a novel application of filamentous bacteriophages (phages) as
Iftach Yacoby; Marina Shamis; Hagit Bar; Doron Shabat; Itai Benhar
The apicomplexan parasite Toxoplasma gondii expresses type II NADH dehydrogenases (NDH2s) instead of canonical complex I at the inner mitochondrial membrane. These non-proton-pumping enzymes are considered to be promising drug targets due to their absence in mammalian cells. We recently showed by inhibition kinetics that T. gondii NDH2-I is a target of the quinolone-like compound 1-hydroxy-2-dodecyl-4(1H)quinolone (HDQ), which inhibits T. gondii replication in the nanomolar range. In this study, the cationic fluorescent probes Mitotracker and DiOC6(3) (3,3?-dihexyloxacarbocyanine iodine) were used to monitor the influence of HDQ on the mitochondrial inner membrane potential (??m) in T. gondii. Real-time imaging revealed that nanomolar HDQ concentrations led to a ??m collapse within minutes, which is followed by severe ATP depletions of 30% after 1 h and 70% after 24 h. ??m depolarization was attenuated when substrates for other dehydrogenases that can donate electrons to ubiquinone were added to digitonin-permeabilized cells or when infected cultures were treated with the Fo-ATPase inhibitor oligomycin. A prolonged treatment with sublethal concentrations of HDQ induced differentiation into bradyzoites. This dormant stage is likely to be less dependent on the ??m, since ??m-positive parasites were found at a significantly lower frequency in alkaline-pH-induced bradyzoites than in tachyzoites. Together, our studies reveal that oxidative phosphorylation is essential for maintaining the ATP level in the fast-growing tachyzoite stage and that HDQ interferes with this pathway by inhibiting the electron transport chain at the level of ubiquinone reduction.
Lin, San San; Gross, Uwe; Bohne, Wolfgang
Growth Inhibition of Toxoplasma gondii and Plasmodium falciparum by Nanomolar Concentrations of 1-Hydroxy-2-Dodecyl-4(1H)Quinolone, a High-Affinity Inhibitor of Alternative (Type II) NADH Dehydrogenases?
Both apicomplexan parasites Toxoplasma gondii and Plasmodium falciparum lack type I NADH dehydrogenases (complex I) but instead carry alternative (type II) NADH dehydrogenases, which are absent in mammalian cells and are thus considered promising antimicrobial drug targets. The quinolone-like compound 1-hydroxy-2-dodecyl-4(1H)quinolone (HDQ) was recently described as a high-affinity inhibitor of fungal alternative NADH dehydrogenases in enzymatic assays, probably by interfering with the ubiquinol binding site of the enzyme. We describe here that HDQ effectively inhibits the replication rates of P. falciparum and T. gondii in tissue culture. The 50% inhibitory concentration (IC50) of HDQ for T. gondii was determined to be 2.4 ± 0.3 nM with a growth assay based on vacuole sizes and 3.7 ± 1.4 nM with a growth assay based on beta-galactosidase activity. Quantification of the P. falciparum replication rate using a fluorometric assay revealed an IC50 of 14.0 ± 1.9 nM. An important feature of the HDQ structure is the length of the alkyl side chain at position 2. Derivatives with alkyl side chains of C6, C8, C12 (HDQ), and C14 all displayed excellent anti-T. gondii activity, while a C5 derivative completely failed to inhibit parasite replication. A combined treatment of T. gondii-infected cells with HDQ and the antimalarial agent atovaquone, which blocks the ubiquinol oxidation site of cytochrome b in complex III, resulted in synergism, with a calculated fractional inhibitory concentration of 0.16 nM. Interference of the mitochondrial ubiquinone/ubiquinol cycle at two different locations thus appears to be a highly effective strategy for inhibiting parasite replication. HDQ and its derivatives, particularly in combination with atovaquone, represent promising compounds with a high potential for antimalarial and antitoxoplasmal therapy.
Saleh, Ahmad; Friesen, Johannes; Baumeister, Stefan; Gross, Uwe; Bohne, Wolfgang
Little is known about the correlation between genotype and drug susceptibility in Mycobacterium avium (Mav) strains isolated from patients with Mav infections. To examine whether drug susceptibility profile of Mav is associated with genotype, we carried out variable-number tandem-repeat (VNTR) typing and drug susceptibility testing for Mav isolates from Japanese with nodular-bronchiectasis (NB)-type and cavitary disease (CA)-type diseases. We performed M. avium tandem repeat (MATR)-VNTR typing and drug susceptibility testing by the broth dilution method, using macrolides, rifamycins, ethambutol, isoniazid, aminoglycosides, and quinolones, for Mav isolates from patients with NB and CA-type diseases (NB-Mav and CA-Mav). Based on the VNTR genotyping, the Mav strains were grouped into three clusters. There was no difference with respect to the distribution of NB-Mav and CA-Mav among the clusters. We observed a strong association between VNTR genotype and susceptibility to quinolones (levofloxacin, moxifloxacin, gatifloxacin, sitafloxacin, and garenoxacin) and ethambutol. There was essentially no significant difference in drug susceptibility between NB- and CA-Mav strains, although NB-Mav was somewhat more resistant to fluoroquinolones, espec