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Journal articles on the topic 'Quinolone'
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1
Shoji, Taku, Mutsumi Takeuchi, Mayumi Uda, Yukino Ariga, Akari Yamazaki, Ryuta Sekiguchi, and Shunji Ito. "Synthesis of Azuleno[2,1-b]quinolones and Quinolines via Brønsted Acid-Catalyzed Cyclization of 2-Arylaminoazulenes." Molecules 28, no. 15 (July 31, 2023): 5785. http://dx.doi.org/10.3390/molecules28155785.
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Quinolone and quinoline derivatives are frequently found as substructures in pharmaceutically active compounds. In this paper, we describe a procedure for the synthesis of azuleno[2,1-b]quinolones and quinolines from 2-arylaminoazulene derivatives, which are readily prepared via the aromatic nucleophilic substitution reaction of a 2-chloroazulene derivative with several arylamines. The synthesis of azuleno[2,1-b]quinolones was established by the Brønsted acid-catalyzed intramolecular cyclization of 2-arylaminoazulene derivatives bearing two ester groups at the five-membered ring. The halogenative aromatization of azuleno[2,1-b]quinolones with POCl3 yielded azuleno[2,1-b]quinolines with a chlorine substituent at the pyridine moiety. The aromatic nucleophilic substitution reaction of azuleno[2,1-b]quinolines bearing chlorine substituent with secondary amines was also investigated to afford the aminoquinoline derivatives. These synthetic methodologies reported in this paper should be valuable in the development of new pharmaceuticals based on the azulene skeleton.
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Ehrhardt, A. F., and C. C. Sanders. "Structure-activity studies of quinolone-penems in genetically defined strains of Escherichia coli." Antimicrobial Agents and Chemotherapy 41, no. 11 (November 1997): 2570–72. http://dx.doi.org/10.1128/aac.41.11.2570.
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Quinolonyl-beta-lactam antimicrobial agents (QLAs) contain quinolones chemically linked to beta-lactams, although the impact of linkage is poorly understood. Genetically defined Escherichia coli strains were used to determine structure-activity characteristics of three quinolone-penem QLAs. Results suggest that the leaving group resulting from beta-lactam hydrolysis may not be free quinolone.
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Kumagai, Y., J. I. Kato, K. Hoshino, T. Akasaka, K. Sato, and H. Ikeda. "Quinolone-resistant mutants of escherichia coli DNA topoisomerase IV parC gene." Antimicrobial Agents and Chemotherapy 40, no. 3 (March 1996): 710–14. http://dx.doi.org/10.1128/aac.40.3.710.
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Escherichia coli quinolone-resistant strains with mutations of the parC gene, which codes for a subunit of topoisomerase IV, were isolated from a quinolone-resistant gyrA mutant of DNA gyrase. Quinolone-resistant parC mutants were also identified among the quinolone-resistant clinical strains. The parC mutants became susceptible to quinolones by introduction of a parC+ plasmid. Introduction of the multicopy plasmids carrying the quinolone-resistant parC mutant gene resulted in an increase in MICs of quinolones for the parC+ and quinolone-resistant gyrA strain. Nucleotide sequences of the quinolone-resistant parC mutant genes were determined, and missense mutations at position Gly-78, Ser-80, or Glu-84, corresponding to those in the quinolone-resistance-determining region of DNA gyrase, were identified. These results indicate that topoisomerase IV is a target of quinolones in E. coli and suggest that the susceptibility of E. coli cells to quinolones is determined by sensitivity of the targets, DNA gyrase and topoisomerase IV.
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Noble, Christian G., Faye M. Barnard, and Anthony Maxwell. "Quinolone-DNA Interaction: Sequence-Dependent Binding to Single-Stranded DNA Reflects the Interaction within the Gyrase-DNA Complex." Antimicrobial Agents and Chemotherapy 47, no. 3 (March 2003): 854–62. http://dx.doi.org/10.1128/aac.47.3.854-862.2003.
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ABSTRACT We have investigated the interaction of quinolones with DNA by a number of methods to establish whether a particular binding mode correlates with quinolone potency. The specificities of the quinolone-mediated DNA cleavage reaction of DNA gyrase were compared for a number of quinolones. Two patterns that depended on the potency of the quinolone were identified. Binding to plasmid DNA was examined by measuring the unwinding of pBR322 by quinolones; no correlation with quinolone potency was observed. Quinolone binding to short DNA oligonucleotides was measured by surface plasmon resonance. The quinolones bound to both single- and double-stranded oligonucleotides in an Mg2+-dependent manner. Quinolones bound to single-stranded DNA with a higher affinity, and the binding exhibited sequence dependence; binding to double-stranded DNA was sequence independent. The variations in binding in the presence of metal ions showed that Mg2+ promoted tighter, more specific binding to single-stranded DNA than softer metal ions (Mn2+ and Cd2+). Single-stranded DNA binding by quinolones correlated with the in vitro quinolone potency, indicating that this mode of interaction may reflect the interaction of the quinolone with DNA in the context of the gyrase-DNA complex.
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Horta, Pedro, Marta S. C. Henriques, Elisa M. Brás, Fernanda Murtinheira, Fátima Nogueira, Paul M. O’Neill, José A. Paixão, Rui Fausto, and Maria L. S. Cristiano. "On the ordeal of quinolone preparation via cyclisation of aryl-enamines; synthesis and structure of ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylate." Pure and Applied Chemistry 89, no. 6 (June 27, 2017): 765–80. http://dx.doi.org/10.1515/pac-2016-1119.
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AbstractRecent studies directed to the design of compounds targeting the bc1 protein complex of Plasmodium falciparum, the parasite responsible for most lethal cases of malaria, identified quinolones (4-oxo-quinolines) with low nanomolar inhibitory activity against both the enzyme and infected erythrocytes. The 4-oxo-quinoline 3-ester chemotype emerged as a possible source of potent bc1 inhibitors, prompting us to expand the library of available analogs for SAR studies and subsequent lead optimization. We now report the synthesis and structural characterization of unexpected ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylate, a 4-aryloxy-quinoline 3-ester formed during attempted preparation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate (4-oxo-quinoline 3-ester). We propose that the 4-aryloxy-quinoline 3-ester derives from 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate (4-hydroxy-quinoline 3-ester), the enol form of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate. Formation of the 4-aryloxy-quinoline 3-ester confirms the impact of quinolone/hydroxyquinoline tautomerism, both on the efficiency of synthetic routes to quinolones and on pharmacologic profiles. Tautomers exhibit different cLogP values and interact differently with the enzyme active site. A structural investigation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate and 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, using matrix isolation coupled to FTIR spectroscopy and theoretical calculations, revealed that the lowest energy conformers of 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, lower in energy than their most stable 4-oxo-quinoline tautomer by about 27 kJ mol−1, are solely present in the matrix, while the most stable 4-oxo-quinoline tautomer is solely present in the crystalline phase.
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López, Y., M. Tato, P. Espinal, F. Garcia-Alonso, D. Gargallo-Viola, R. Cantón, and J. Vila. "In VitroActivity of Ozenoxacin against Quinolone-Susceptible and Quinolone-Resistant Gram-Positive Bacteria." Antimicrobial Agents and Chemotherapy 57, no. 12 (September 30, 2013): 6389–92. http://dx.doi.org/10.1128/aac.01509-13.
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ABSTRACTIn vitroactivity of ozenoxacin, a novel nonfluorinated topical (L. D. Saravolatz and J. Leggett, Clin. Infect. Dis.37:1210–1215, 2003) quinolone, was compared with the activities of other quinolones against well-characterized quinolone-susceptible and quinolone-resistant Gram-positive bacteria. Ozenoxacin was 3-fold to 321-fold more active than other quinolones. Ozenoxacin could represent a first-in-class nonfluorinated quinolone for the topical treatment of a broad range of dermatological infections.
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Adriaenssens, Niels, Robin Bruyndonckx, Ann Versporten, Niel Hens, Dominique L. Monnet, Geert Molenberghs, Herman Goossens, et al. "Consumption of quinolones in the community, European Union/European Economic Area, 1997–2017." Journal of Antimicrobial Chemotherapy 76, Supplement_2 (July 1, 2021): ii37—ii44. http://dx.doi.org/10.1093/jac/dkab176.
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Abstract Objectives Data on quinolone consumption in the community were collected from 30 EU/European Economic Area (EEA) countries over two decades. This article reviews temporal trends, seasonal variation, presence of change-points and changes in the composition of main subgroups of quinolones. Methods For the period 1997–2017, data on consumption of quinolones, i.e. ATC group J01M, in the community and aggregated at the level of the active substance, were collected using the WHO ATC/DDD methodology (ATC/DDD index 2019). Consumption was expressed in DDD per 1000 inhabitants per day and in packages per 1000 inhabitants per day. Quinolone consumption was analysed by subgroups based on pharmacokinetic profile, and presented as trends, seasonal variation, presence of change-points and compositional changes. Results In 2017, quinolone consumption in the community expressed in DDD per 1000 inhabitants per day varied by a factor of 8.2 between countries with the highest (Bulgaria) and the lowest (Norway) consumption. The second-generation quinolones accounted for >50% of quinolone consumption in most countries. Quinolone consumption significantly increased up to 2001, and did not change significantly afterwards. Seasonal variation increased significantly over time. Proportional consumption of third-generation quinolones significantly increased over time relative to that of second-generation quinolones, while proportional consumption of both third- and second-generation quinolones significantly increased relative to that of first-generation quinolones. Levofloxacin and moxifloxacin represented >40% of quinolone consumption in the community in southern EU/EEA countries. Conclusions Quinolone consumption in the community is no longer increasing in the EU/EEA, but its seasonal variation continues to increase significantly as is the proportion of quinolones to treat respiratory infections.
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McGee, Edoabasi U., Essie Samuel, Bernadett Boronea, Nakoasha Dillard, Madison N. Milby, and Susan J. Lewis. "Quinolone Allergy." Pharmacy 7, no. 3 (July 19, 2019): 97. http://dx.doi.org/10.3390/pharmacy7030097.
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Quinolones are the second most common antibiotic class associated with drug-induced allergic reactions, but data on quinolone allergy are scarce. This review article discusses the available evidence on quinolone allergy, including prevalence, risk factors, diagnosis, clinical manifestations, cross-reactivity, and management of allergic reactions. Although the incidence of quinolone allergy is still lower than beta-lactams, it has been increasingly reported in recent decades, most likely from its expanded use and the introduction of moxifloxacin. Thorough patient history remains essential in the evaluation of quinolone allergy. Many diagnostic tools have been investigated, but skin tests can yield false-positive results and in vitro tests have not been validated. The drug provocation test is considered the test of choice to confirm a quinolone allergy but is not without risk. Evidence regarding cross-reactivity among the quinolones is limited and conflicting. Quinolone allergy can be manifested either as an immediate or delayed reaction, but is not uniform across the class, with moxifloxacin posing the highest risk of anaphylaxis. Quinolone should be discontinued when an allergic reaction occurs and avoided in future scenarios, but desensitization may be warranted if no alternatives are available.
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Law, Dennis KS, Michelle Shuel, Sadjia Bekal, Elizabeth Bryce, and Raymond SW Tsang. "Genetic Detection of Quinolone Resistance inHaemophilus parainfluenzae: Mutations in the Quinolone Resistance-Determining Regions ofgyrA andparC." Canadian Journal of Infectious Diseases and Medical Microbiology 21, no. 1 (2010): e20-e22. http://dx.doi.org/10.1155/2010/525919.
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The quinolone resistance-determining regions ofgyrA andparC of both quinolone-sensitive and quinolone-resistantHaemophilus parainfluenzaestrains were amplified and sequenced. Similar toHaemophilus influenzae, resistance to quinolones inH parainfluenzaeis associated with mutations in the quinolone resistance-determining regions of bothgyrA andparC. The present study discusses the importance of this finding.
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Wang, Xiaoli, Tao Guo, Yunbo Wei, Guiju Xu, Na Li, Jinhong Feng, and Rusong Zhao. "Determination of Quinolone Antibiotic Residues in Human Serum and Urine Using High-Performance Liquid Chromatography/Tandem Mass Spectrometry." Journal of Analytical Toxicology 43, no. 7 (May 16, 2019): 579–86. http://dx.doi.org/10.1093/jat/bkz034.
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Abstract Quinolone antibiotic residues may pose potential threat to human health. A rapid and sensitive method was developed for the determination of quinolone residues in human serum and urine. After solid phase extraction (SPE) process, eight quinolone residues were analyzed by high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) using ciprofloxacin-d8 as the internal standard. The relative standard deviation of intra-day and inter-day precision for the eight quinolones were less than 7.52% and the accuracies ranged from 95.8% to 103% in human serum, and from 94.1% to 104% in human urine. The extraction recoveries for the eight quinolones varied from 80.2% to 113% in human serum and 83.4% to 117% in human urine. The limit of detection for the eight quinolones was 0.50–1.00 ng/mL. Quinolone antibiotic residues in human serum and urine from 12 volunteers were successfully analyzed with the validated method. The SPE-HPLC-MS/MS method was useful for accurate determination of quinolone antibiotic residues in human body.
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Gottesman, Bat-Sheva, Marcelo Low, Ronit Almog, and Michal Chowers. "Quinolone Consumption by Mothers Increases Their Children’s Risk of Acquiring Quinolone-Resistant Bacteriuria." Clinical Infectious Diseases 71, no. 3 (August 29, 2019): 532–38. http://dx.doi.org/10.1093/cid/ciz858.
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Abstract Background Quinolone resistance has been documented in the pediatric population, although their use is limited in children. This study investigated the effect of maternal quinolone use on gram-negative bacterial resistance to quinolones in their offspring. Methods We conducted a population-based, unmatched case-control study during 2010–2017. Cases were all children aged 0.5–17 years with community acquired, gram-negative quinolone-resistant bacteriuria. Controls were similar children with quinolone-sensitive bacteriuria. Only the first positive urine cultures for each child were included. Data on quinolones dispensed to the mother, any antibiotics dispensed to the children, age, sex, ethnicity, and prior hospitalizations were collected. Children with previous quinolone use were excluded. Results The study population consisted of 40 204 children. Quinolone resistance was detected in 2182 (5.3%) urine cultures. The median age was 5 years, with 93.7% females and 77.6% Jewish. A total of 26 937 (65%) of the children received any antibiotic and 1359 (3.2%) of the mothers received quinolones in the 6 months preceding bacteriuria. Independent risk factors were quinolone dispensed to the mothers (odds ratio [OR], 1.50 [95% confidence interval {CI}, 1.22–1.85]), Arab ethnicity (OR, 1.99 [95% CI, 1.81–2.19]), and antibiotic dispensed to the child (OR, 1.54 [95% CI, 1.38–1.71]). Compared with children aged 12–17 years, younger children had 1.33–1.43 increased odds for quinolone-resistant bacteriuria. Conclusions Quinolone prescription to mothers was linked to increased risk of community-acquired, quinolone-resistant bacteria in their offspring, by about 50%. This is another example of the deleterious ecological effects of antibiotic use and should be considered when prescribing antibiotics.
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Azargun, Robab, Pourya Gholizadeh, Vahid Sadeghi, Hasan Hosainzadegan, Vahideh Tarhriz, Mohammad Yousef Memar, Ali Pormohammad, and Shirin Eyvazi. "Molecular mechanisms associated with quinolone resistance in Enterobacteriaceae: review and update." Transactions of The Royal Society of Tropical Medicine and Hygiene 114, no. 10 (July 1, 2020): 770–81. http://dx.doi.org/10.1093/trstmh/traa041.
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Abstract Background Quinolones are broad-spectrum antibiotics, which are used for the treatment of different infectious diseases associated with Enterobacteriaceae. During recent decades, the wide use as well as overuse of quinolones against diverse infections has led to the emergence of quinolone-resistant bacterial strains. Herein, we present the development of quinolone antibiotics, their function and also the different quinolone resistance mechanisms in Enterobacteriaceae by reviewing recent literature. Methods All data were extracted from Google Scholar search engine and PubMed site, using keywords; quinolone resistance, Enterobacteriaceae, plasmid-mediated quinolone resistance, etc. Results and conclusion The acquisition of resistance to quinolones is a complex and multifactorial process. The main resistance mechanisms consist of one or a combination of target-site gene mutations altering the drug-binding affinity of target enzymes. Other mechanisms of quinolone resistance are overexpression of AcrAB-tolC multidrug-resistant efflux pumps and downexpression of porins as well as plasmid-encoded resistance proteins including Qnr protection proteins, aminoglycoside acetyltransferase (AAC(6′)-Ib-cr) and plasmid-encoded active efflux pumps such as OqxAB and QepA. The elucidation of resistance mechanisms will help researchers to explore new drugs against the resistant strains.
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Spencer, Angela C., and Siva S. Panda. "DNA Gyrase as a Target for Quinolones." Biomedicines 11, no. 2 (January 27, 2023): 371. http://dx.doi.org/10.3390/biomedicines11020371.
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Bacterial DNA gyrase is a type II topoisomerase that can introduce negative supercoils to DNA substrates and is a clinically-relevant target for the development of new antibacterials. DNA gyrase is one of the primary targets of quinolones, broad-spectrum antibacterial agents and are used as a first-line drug for various types of infections. However, currently used quinolones are becoming less effective due to drug resistance. Common resistance comes in the form of mutation in enzyme targets, with this type being the most clinically relevant. Additional mechanisms, conducive to quinolone resistance, are arbitrated by chromosomal mutations and/or plasmid-gene uptake that can alter quinolone cellular concentration and interaction with the target, or affect drug metabolism. Significant synthetic strategies have been employed to modify the quinolone scaffold and/or develop novel quinolones to overcome the resistance problem. This review discusses the development of quinolone antibiotics targeting DNA gyrase to overcome bacterial resistance and reduce toxicity. Moreover, structural activity relationship (SAR) data included in this review could be useful for the development of future generations of quinolone antibiotics.
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Saleh, Fatma O. I., Hazem A. Ahmed, Rasha M. M. Khairy, and Sayed F. Abdelwahab. "Increased quinolone resistance among typhoid Salmonella isolated from Egyptian patients." Journal of Infection in Developing Countries 8, no. 05 (May 14, 2014): 661–65. http://dx.doi.org/10.3855/jidc.4111.
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Introduction: Typhoid fever is endemic in Egypt; and quinolones are the empirical treatment of choice. There are very limited data reporting quinolone resistance among Egyptian typhoidal Salmonella isolates. We previously reported that all typhoidal Salmonella were sensitive to quinolones. This study aimed to isolate and identify typhoidal Salmonella from cases suffering from enteric fever at Minia Governorate, Egypt, determine their quinolone resistance patterns, compare them to those reported 20 years ago, and test gyrA mutation as a possible mechanism for quinolone resistance. Methodology: Stool samples from Widal-positive subjects were screened by culture on suitable media and were identified biochemically. The identified isolates were tested for resistance against three representatives of the first three quinolone generations, namely nalidixic acid (NAL), levofloxacin (LEV), and norfloxacin (NOR). The gyrA gene was amplified and sequenced to detect point mutation(s) conferring quinolone resistance. Results: Out of 230 stool samples (from patients with Widal anti-O titers of ≥ 1/160), 40 isolates were S. enterica serovar Typhi (97.5%) and Paratyphi A (2.5%). Six (15%) isolates were resistant to at least one of the quinolones, compared to 0% in 1993. In this regard, 15%, 7.5%, and 2.5% of the isolates were resistant to NAL, both NAL and LEV, and all three quinolones tested, respectively. Sequencing of the gyrA gene revealed point mutations at position 83 and/or 87 of the gyrA gene only among the resistant isolates. Conclusion: There has been an increase in quinolone-resistant typhoidal Salmonella in Egypt over time.
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Wickman, Paul A., Jennifer A. Black, Ellen Smith Moland, and Kenneth S. Thomson. "In Vitro Activities of DX-619 and Comparison Quinolones against Gram-Positive Cocci." Antimicrobial Agents and Chemotherapy 50, no. 6 (June 2006): 2255–57. http://dx.doi.org/10.1128/aac.00011-06.
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ABSTRACT The in vitro activity of the novel quinolone DX-619 was compared to those of currently available quinolones against U.S. clinical isolates of Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus spp., Streptococcus pyogenes, and Streptococcus pneumoniae. DX-619 was the most potent quinolone overall, indicating possible utility as an anti-gram-positive quinolone.
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Xia, Yi, Zheng-Yu Yang, Susan L. Morris-Natschke, and Kuo-Hsiung Lee. "Recent Advances in the Discovery and Development of Quinolones and Analogs as Antitumor Agents'." Current Medicinal Chemistry 6, no. 3 (March 1999): 179–94. http://dx.doi.org/10.2174/0929867306666220208204749.
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Abstract: Compounds that interact with DNA or microtubules by multiple mechanisms and cause diverse cytotoxic lesions are potential targets for anticancer drug development. Accordingly, a relatively new approach to the rational design of antitumor agents is based on the quinolone class of antibacterials. Their mechanism of antibacterial action involves inhibition of DNA gyrase, and numerous new quinolones do exhibit antitumor activity. Thus, these new quinolone structures display a novel mode of action for the quinolone class as antitumor agents. The potential for quinolones to be used as topoisomerase II inhibitors, as well as antimitotic agents, is reviewed with a focus on recent discoveries and development of antitumor quinolones, especially related work in the author's laboratory.
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Corrêa, Gabriela A., Susana L. H. Rebelo, and Baltazar de Castro. "Green Aromatic Epoxidation with an Iron Porphyrin Catalyst for One-Pot Functionalization of Renewable Xylene, Quinoline, and Acridine." Molecules 28, no. 9 (May 7, 2023): 3940. http://dx.doi.org/10.3390/molecules28093940.
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Sustainable functionalization of renewable aromatics is a key step to supply our present needs for specialty chemicals and pursuing the transition to a circular, fossil-free economy. In the present work, three typically stable aromatic compounds, representative of products abundantly obtainable from biomass or recycling processes, were functionalized in one-pot oxidation reactions at room temperature, using H2O2 as a green oxidant and ethanol as a green solvent in the presence of a highly electron withdrawing iron porphyrin catalyst. The results show unusual initial epoxidation of the aromatic ring by the green catalytic system. The epoxides were isolated or evolved through rearrangement, ring opening by nucleophiles, and oxidation. Acridine was oxidized to mono- and di-oxides in the peripheral ring: 1:2-epoxy-1,2-dihydroacridine and anti-1:2,3:4-diepoxy-1,2,3,4-tetrahydroacridine, with TON of 285. o-Xylene was oxidized to 4-hydroxy-3,4-dimethylcyclohexa-2,5-dienone, an attractive building block for synthesis, and 3,4-dimethylphenol as an intermediate, with TON of 237. Quinoline was directly functionalized to 4-quinolone or 3-substituted-4-quinolones (3-ethoxy-4-quinolone or 3-hydroxy-4-quinolone) and corresponding hydroxy-tautomers, with TON of 61.
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Engels, E. A., J. Lau, and M. Barza. "Efficacy of quinolone prophylaxis in neutropenic cancer patients: a meta-analysis." Journal of Clinical Oncology 16, no. 3 (March 1998): 1179–87. http://dx.doi.org/10.1200/jco.1998.16.3.1179.
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PURPOSE To perform a meta-analysis to estimate the efficacy of quinolone antibiotics in preventing infections, fevers, and deaths among cancer patients neutropenic following chemotherapy. METHODS We searched MEDLINE to identify randomized trials of quinolone prophylaxis, controlled either with no prophylaxis or trimethoprim/sulfamethoxazole (TMS) prophylaxis. We pooled relative risks for outcomes using a random-effects model. RESULTS Eighteen trials with 1,408 subjects were included. Compared with no prophylaxis, quinolones significantly reduced the incidence of gram-negative bacterial infections (relative risk, 0.21; 95% confidence interval [CI], 0.12 to 0.37), microbiologically documented infections (0.65; 0.50 to 0.85), total infections (0.54; 0.31 to 0.95), and fevers (0.85; 0.73 to 0.99). Quinolone prophylaxis did not alter the incidence of gram-positive bacterial, fungal, or clinically documented infections, or infection-related deaths. Results were similar for trials that used TMS as the control regimen. Among those who received quinolones, the incidence of infections due to quinolone-resistant organisms was 3.0% (95% CI, 1.7% to 5.2%) for gram-negative species and 9.4% (95% CI, 5.3% to 16.3%) for gram-positive species. Based on limited data, the incidence of quinolone-resistant infections was not higher among quinolone recipients than controls. With fever as outcome, blinded trials found quinolones less efficacious than did unblinded trials. CONCLUSION Quinolone prophylaxis substantially reduces the incidence of various infection-related outcomes, but not deaths, in these patients. Although this reduction in infections may translate into a decrease in morbidity, the reduction in fevers (and by extension, use of empiric antibiotics) appears small, and blinded trials provided less evidence for benefit than unblinded trials. Quinolone-resistant infections are uncommon, but continued vigilance is warranted.
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Oh, Herin, Nagwa El Amin, Todd Davies, Peter C. Appelbaum, and Charlotta Edlund. "gyrA Mutations Associated with Quinolone Resistance in Bacteroides fragilis Group Strains." Antimicrobial Agents and Chemotherapy 45, no. 7 (July 1, 2001): 1977–81. http://dx.doi.org/10.1128/aac.45.7.1977-1981.2001.
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ABSTRACT Mutations in the gyrA gene contribute considerably to quinolone resistance in Escherichia coli. Mechanisms for quinolone resistance in anaerobic bacteria are less well studied. TheBacteroides fragilis group are the anaerobic organisms most frequently isolated from patients with bacteremia and intraabdominal infections. Forty-four clinafloxacin-resistant and-susceptible fecal and clinical isolates of the B. fragilis group (eightBacteroides fragilis, three Bacteroides ovatus, five Bacteroides thetaiotaomicron, six Bacteroides uniformis, and 22 Bacteroides vulgatus) and six ATCC strains of the B. fragilis group were analyzed as follows: (i) determination of susceptibility to ciprofloxacin, levofloxacin, moxifloxacin, and clinafloxacin by the agar dilution method and (ii) sequencing of the gyrA quinolone resistance-determining region (QRDR) located between amino acid residues equivalent to Ala-67 through Gln-106 in E. coli. Amino acid substitutions were found at hotspots at positions 82 (n = 15) and 86 (n = 8). Strains with Ser82Leu substitutions (n = 13) were highly resistant to all quinolones tested. Mutations in other positions of gyrA were also frequently found in quinolone-resistant and -susceptible isolates. Eight clinical strains that lacked mutations in their QRDR were susceptible to at least two of the quinolones tested. Although newer quinolones have good antimicrobial activity against the B. fragilis group, quinolone resistance in B. fragilisstrains can be readily selected in vivo. Mutational events in the QRDR of gyrA seem to contribute to quinolone resistance inBacteroides species.
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Miranda, Claudio D., Christopher Concha, Félix A. Godoy, and Matthew R. Lee. "Aquatic Environments as Hotspots of Transferable Low-Level Quinolone Resistance and Their Potential Contribution to High-Level Quinolone Resistance." Antibiotics 11, no. 11 (October 27, 2022): 1487. http://dx.doi.org/10.3390/antibiotics11111487.
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The disposal of antibiotics in the aquatic environment favors the selection of bacteria exhibiting antibiotic resistance mechanisms. Quinolones are bactericidal antimicrobials extensively used in both human and animal medicine. Some of the quinolone-resistance mechanisms are encoded by different bacterial genes, whereas others are the result of mutations in the enzymes on which those antibiotics act. The worldwide occurrence of quinolone resistance genes in aquatic environments has been widely reported, particularly in areas impacted by urban discharges. The most commonly reported quinolone resistance gene, qnr, encodes for the Qnr proteins that protect DNA gyrase and topoisomerase IV from quinolone activity. It is important to note that low-level resistance usually constitutes the first step in the development of high-level resistance, because bacteria carrying these genes have an adaptive advantage compared to the highly susceptible bacterial population in environments with low concentrations of this antimicrobial group. In addition, these genes can act additively with chromosomal mutations in the sequences of the target proteins of quinolones leading to high-level quinolone resistance. The occurrence of qnr genes in aquatic environments is most probably caused by the release of bacteria carrying these genes through anthropogenic pollution and maintained by the selective activity of antimicrobial residues discharged into these environments. This increase in the levels of quinolone resistance has consequences both in clinical settings and the wider aquatic environment, where there is an increased exposure risk to the general population, representing a significant threat to the efficacy of quinolone-based human and animal therapies. In this review the potential role of aquatic environments as reservoirs of the qnr genes, their activity in reducing the susceptibility to various quinolones, and the possible ways these genes contribute to the acquisition and spread of high-level resistance to quinolones will be discussed.
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Yamaguchi, Yuko, Masaya Takei, Ryuta Kishii, Mitsuru Yasuda, and Takashi Deguchi. "Contribution of Topoisomerase IV Mutation to Quinolone Resistance in Mycoplasma genitalium." Antimicrobial Agents and Chemotherapy 57, no. 4 (January 28, 2013): 1772–76. http://dx.doi.org/10.1128/aac.01956-12.
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ABSTRACTThe mechanism of quinolone resistance inMycoplasma genitaliumremains poorly understood due to difficulties within vitroculture, 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 ofM. genitaliumharboring substitutions in theparCorparEgenein vitroand to measure the inhibitory activities against the purified topoisomerases ofM. genitalium.
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TANRIVERDİ ÇAYCI, Yeliz, İlknur BIYIK, Kemal BİLGİN, Demet GÜR VURAL, and Asuman BİRİNCİ. "Investigation of plasmid-mediated quinolone resistance genes in carbapenem resistant Enterobacterales." Journal of Experimental and Clinical Medicine 39, no. 2 (March 18, 2022): 429–33. http://dx.doi.org/10.52142/omujecm.39.2.23.
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Fluoroquinolones, 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 quinolo 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 carbapenem resistant Enterobacterales isolates. A total 154 carbapenem resistant Enterobacterales isolates were included in the study. Presence of qnrA, qnrB, qnrC, qnrD and qnrS genes were investigated by multiplex polymerase chain reaction (PCR) method. The results of the PCR amplification revealed that qnrA was detected in two isolates (E6, E85) (1.29%), qnrB was detected in 12 isolates (8.4%) (E32, E43, E46, E61, E62, E84, E94, E149, E 166, E167, E177, E179) and qnrS was detected in six isolates (E15, E25, E57, E63, E70, E80) (4.54%). And one isolate (E9) was both positive for qnrB and qnrS. QnrC and qnrD were not detected in any isolates. 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.
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Kim, Hyun, Chie Nakajima, Kazumasa Yokoyama, Zeaur Rahim, Youn Uck Kim, Hiroki Oguri, and Yasuhiko Suzuki. "Impact of the E540V Amino Acid Substitution in GyrB ofMycobacterium tuberculosison Quinolone Resistance." Antimicrobial Agents and Chemotherapy 55, no. 8 (June 6, 2011): 3661–67. http://dx.doi.org/10.1128/aac.00042-11.
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ABSTRACTAmino acid substitutions conferring resistance to quinolones inMycobacterium tuberculosishave generally been found within the quinolone resistance-determining regions (QRDRs) in the A subunit of DNA gyrase (GyrA) rather than the B subunit of DNA gyrase (GyrB). To clarify the contribution of an amino acid substitution, E540V, in GyrB to quinolone resistance inM. tuberculosis, we expressed recombinant DNA gyrases inEscherichia coliand characterized themin vitro. Wild-type and GyrB-E540V DNA gyrases were reconstitutedin vitroby mixing recombinant GyrA and GyrB. Correlation between the amino acid substitution and quinolone resistance was assessed by the ATP-dependent DNA supercoiling assay, quinolone-inhibited supercoiling assay, and DNA cleavage assay. The 50% inhibitory concentrations of eight quinolones against DNA gyrases bearing the E540V amino acid substitution in GyrB were 2.5- to 36-fold higher than those against the wild-type enzyme. Similarly, the 25% maximum DNA cleavage concentrations were 1.5- to 14-fold higher for the E540V gyrase than for the wild-type enzyme. We further demonstrated that the E540V amino acid substitution influenced the interaction between DNA gyrase and the substituent(s) at R-7, R-8, or both in quinolone structures. This is the first detailed study of the contribution of the E540V amino acid substitution in GyrB to quinolone resistance inM. tuberculosis.
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Heddle, Jonathan, and Anthony Maxwell. "Quinolone-Binding Pocket of DNA Gyrase: Role of GyrB." Antimicrobial Agents and Chemotherapy 46, no. 6 (June 2002): 1805–15. http://dx.doi.org/10.1128/aac.46.6.1805-1815.2002.
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ABSTRACT DNA gyrase is a prokaryotic type II topoisomerase and a major target of quinolone antibacterials. The majority of mutations conferring resistance to quinolones arise within the quinolone resistance-determining region of GyrA close to the active site (Tyr122) where DNA is bound and cleaved. However, some quinolone resistance mutations are known to exist in GyrB. Present structural data suggest that these residues lie a considerable distance from the quinolone resistance-determining region, and it is not obvious how they affect quinolone action. We have made and purified two such mutant proteins, GyrB(Asp426→Asn) and GyrB(Lys447→Glu), and characterized them in vitro. We found that the two proteins behave similarly to GyrA quinolone-resistant proteins. We showed that the mutations exert their effect by decreasing the amount of quinolone bound to a gyrase-DNA complex. We suggest that the GyrB residues form part of a quinolone-binding pocket that includes DNA and the quinolone resistance-determining region in GyrA and that large conformational changes during the catalytic cycle of the enzyme allow these regions to come into close proximity.
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Belotindos, Lawrence, Marvin Villanueva, Joel Miguel, Precious Bwalya, Tetsuya Harada, Ryuji Kawahara, Chie Nakajima, Claro Mingala, and Yasuhiko Suzuki. "Prevalence and Characterization of Quinolone-Resistance Determinants in Escherichia coli Isolated from Food-Producing Animals and Animal-Derived Food in the Philippines." Antibiotics 10, no. 4 (April 9, 2021): 413. http://dx.doi.org/10.3390/antibiotics10040413.
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Antimicrobial resistance to quinolones, which constitutes a threat to public health, has been increasing worldwide. In this study, we investigated the prevalence of quinolone-resistant determinants in Escherichia coli not susceptible to quinolones and isolated from food-producing animals and food derived from them, in the Philippines. A total of 791 E. coli strains were isolated in 56.4% of 601 beef, chicken, pork, egg, and milk samples, as well as environmental, cloacal, and rectal swab-collected samples from supermarkets, open markets, abattoirs, and poultry, swine, and buffalo farms. Using the disc diffusion method, it was determined that 78.6% and 55.4% of the isolates were resistant to at least one antimicrobial and multiple drugs, respectively. In 141 isolates not susceptible to quinolones, 115 (81.6%) harbored quinolone-resistant determinants and had mutations predominantly in the quinolone-resistance determining regions (QRDRs) of gyrA and parC. Plasmid-mediated, quinolone resistance (PMQR) and Qnr family (qnrA1, qnrB4, and qnrS1) genes were detected in all isolates. Forty-eight sequence types were identified in isolates harboring mutations in QRDR and/or PMQR genes by multilocus sequence typing analysis. Moreover, 26 isolates harboring mutations in QRDR and/or PMQR genes belonged mostly to phylogroup B1 and Enteroaggregative E. coli. In conclusion, a high prevalence of E. coli was found in food-producing animals and products derived from them, which could potentially spread high-risk clones harboring quinolone-resistance determinants.
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Kumar, Anil, Nishtha Saxena, Arti Mehrotra, and Nivedita Srivastava. "Review: Studies on the Synthesis of Quinolone Derivatives with Their Antibacterial Activity (Part 1)." Current Organic Chemistry 24, no. 8 (June 23, 2020): 817–54. http://dx.doi.org/10.2174/1385272824999200427082108.
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Quinolone derivatives have attracted considerable attention due to their medicinal properties. This review covers many synthetic routes of quinolones preparation with their antibacterial properties. Detailed study with structure-activity relationship among quinolone derivatives will be helpful in designing new drugs in this field.
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Kosowska-Shick, Klaudia, Kim Credito, Glenn A. Pankuch, Gengrong Lin, Bülent Bozdogan, Pamela McGhee, Bonifacio Dewasse, Dong-Rack Choi, Jei Man Ryu, and Peter C. Appelbaum. "Antipneumococcal Activity of DW-224a, a New Quinolone, Compared to Those of Eight Other Agents." Antimicrobial Agents and Chemotherapy 50, no. 6 (June 2006): 2064–71. http://dx.doi.org/10.1128/aac.00153-06.
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ABSTRACT DW-224a is a new broad-spectrum quinolone with excellent antipneumococcal activity. Agar dilution MIC was used to test the activity of DW-224a compared to those of penicillin, ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, gemifloxacin, amoxicillin-clavulanate, cefuroxime, and azithromycin against 353 quinolone-susceptible pneumococci. The MICs of 29 quinolone-resistant pneumococci with defined quinolone resistance mechanisms against seven quinolones and an efflux mechanism were also tested. DW-224a was the most potent quinolone against quinolone-susceptible pneumococci (MIC50, 0.016 μg/ml; MIC90, 0.03 μg/ml), followed by gemifloxacin, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. β-Lactam MICs rose with those of penicillin G, and azithromycin resistance was seen mainly in strains with raised penicillin G MICs. Against the 29 quinolone-resistant strains, DW-224a had the lowest MICs (0.06 to 1 μg/ml) compared to those of gemifloxacin, clinafloxacin, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. DW-224a at 2× MIC was bactericidal after 24 h against eight of nine strains tested. Other quinolones gave similar kill kinetics relative to higher MICs. Serial passages of nine strains in the presence of sub-MIC concentrations of DW-224a, moxifloxacin, levofloxacin, ciprofloxacin, gatifloxacin, gemifloxacin, amoxicillin-clavulanate, cefuroxime, and azithromycin were performed. DW-224a yielded resistant clones similar to moxifloxacin and gemifloxacin but also yielded lower MICs. Azithromycin selected resistant clones in three of the five parents tested. Amoxicillin-clavulanate and cefuroxime did not yield resistant clones after 50 days.
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Wickman, Paul A., Ellen Smith Moland, Jennifer A. Black, and Kenneth S. Thomson. "In Vitro Activity of DX-619, a Novel Des-Fluoro(6) Quinolone, against a Panel of Streptococcus pneumoniae Mutants with Characterized Resistance Mechanisms." Antimicrobial Agents and Chemotherapy 50, no. 2 (February 2006): 796–98. http://dx.doi.org/10.1128/aac.50.2.796-798.2006.
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ABSTRACT The in vitro activities of DX-619 and four other quinolones were compared against Streptococcus pneumoniae mutants that contained a variety of alterations within the quinolone resistance-determining regions. DX-619 was the most potent quinolone and was least affected by the mutations.
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Yagci, D., F. Yoruk, A. Azap, and O. Memikoglu. "Prevalence and Risk Factors for Selection of Quinolone-Resistant Escherichia coli Strains in Fecal Flora of Patients Receiving Quinolone Therapy." Antimicrobial Agents and Chemotherapy 53, no. 3 (December 8, 2008): 1287–89. http://dx.doi.org/10.1128/aac.01228-08.
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ABSTRACT Patients taking quinolones as inpatients (n = 55) or outpatients (n = 40) and newly hospitalized patients who were not on quinolone therapy (n = 41) were assessed for fecal carriage of quinolone-resistant Escherichia coli (QREC) strains before and after therapy/hospitalization. Fluoroquinolone use in the previous 6 months was found to be a risk factor for QREC carriage before therapy/hospitalization. The prevalence of QREC strains in fecal flora increased steadily with the duration of quinolone therapy.
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Yamagishi, J., T. Kojima, Y. Oyamada, K. Fujimoto, H. Hattori, S. Nakamura, and M. Inoue. "Alterations in the DNA topoisomerase IV grlA gene responsible for quinolone resistance in Staphylococcus aureus." Antimicrobial Agents and Chemotherapy 40, no. 5 (May 1996): 1157–63. http://dx.doi.org/10.1128/aac.40.5.1157.
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A 4.2-kb DNA fragment conferring quinolone resistance was cloned from a quinolone-resistant clinical isolate of Staphylococcus aureus and was shown to possess a part of the grlB gene and a mutated grlA gene. S-80-->F and E-84-->K mutations in the grlA gene product were responsible for the quinolone resistance. The mutated grlA genes responsible for quinolone resistance were dominant over the wild-type allele, irrespective of gene dosage in a transformation experiment with the grlA gene alone. However, dominance by mutated grlA genes depended on gene dosage when bacteria were transformed with the grlA and grlB genes in combination. Quinolone-resistant gyrA mutants were easily isolated from a strain, S. aureus RN4220, carrying a plasmid with the mutated grlA gene, though this was not the case for other S. aureus strains lacking the plasmid. The elimination of this plasmid from such quinolone-resistant gyrA mutants resulted in marked increases in quinolone susceptibility. These results suggest that both DNA gyrase and DNA topoisomerase IV may be targets of quinolones and that the quinolone susceptibility of organisms may be determined by which of these enzymes is most quinolone sensitive.
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Hong, Yuzhi, Qiming Li, Qiong Gao, Jianping Xie, Haihui Huang, Karl Drlica, and Xilin Zhao. "Reactive oxygen species play a dominant role in all pathways of rapid quinolone-mediated killing." Journal of Antimicrobial Chemotherapy 75, no. 3 (December 3, 2019): 576–85. http://dx.doi.org/10.1093/jac/dkz485.
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Abstract Background Quinolones have been thought to rapidly kill bacteria in two ways: (i) quinolone-topoisomerase-DNA lesions stimulate the accumulation of toxic reactive oxygen species (ROS); and (ii) the lesions directly cause lethal DNA breaks. Traditional killing assays may have underestimated the ROS contribution by overlooking the possibility that ROS continue to accumulate and kill cells on drug-free agar after quinolone removal. Methods Quinolone-induced, ROS-mediated killing of Escherichia coli was measured by plating post-treatment samples on agar with/without anti-ROS agents. Results When E. coli cultures were treated with ciprofloxacin or moxifloxacin in the presence of chloramphenicol (to accentuate DNA-break-mediated killing), lethal activity, revealed by plating on quinolone-free agar, was inhibited by supplementing agar with ROS-mitigating agents. Moreover, norfloxacin-mediated lethality, observed with cells suspended in saline, was blocked by inhibitors of ROS accumulation and exacerbated by a katG catalase deficiency that impairs peroxide detoxification. Unlike WT cells, the katG mutant was killed by nalidixic acid or norfloxacin with chloramphenicol present and by nalidixic or oxolinic acid with cells suspended in saline. ROS accumulated after quinolone removal with cultures either co-treated with chloramphenicol or suspended in saline. Deficiencies in recA or recB reduced the protective effects of ROS-mitigating agents, supporting the idea that repair of quinolone-mediated DNA lesions suppresses the direct lethal effects of such lesions. Conclusions ROS are the dominant factor in all modes of quinolone-mediated lethality, as quinolone-mediated primary DNA lesions are insufficient to kill without triggering ROS accumulation. ROS-stimulating adjuvants may enhance the lethality of quinolones and perhaps other antimicrobials.
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Rømer Villumsen, Kasper, Toloe Allahghadry, Magdalena Karwańska, Joachim Frey, and Anders Miki Bojesen. "Quinolone Resistance in Gallibacterium anatis Determined by Mutations in Quinolone Resistance-Determining Region." Antibiotics 12, no. 5 (May 13, 2023): 903. http://dx.doi.org/10.3390/antibiotics12050903.
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Control of the important pathogen, Gallibacterium anatis, which causes salpingitis and peritonitis in poultry, relies on treatment using antimicrobial compounds. Among these, quinolones and fluoroquinolones have been used extensively, leading to a rise in the prevalence of resistant strains. The molecular mechanisms leading to quinolone resistance, however, have not previously been described for G. anatis, which is the aim of this study. The present study combines phenotypic antimicrobial resistance data with genomic sequence data from a collection of G. anatis strains isolated from avian hosts between 1979 and 2020. Minimum inhibitory concentrations were determined for nalidixic acid, as well as for enrofloxacin for each included strain. In silico analyses included genome-wide queries for genes known to convey resistance towards quinolones, identification of variable positions in the primary structure of quinolone protein targets and structural prediction models. No resistance genes known to confer resistance to quinolones were identified. Yet, a total of nine positions in the quinolone target protein subunits (GyrA, GyrB, ParC and ParE) displayed substantial variation and were further analyzed. By combining variation patterns with observed resistance patterns, positions 83 and 87 in GyrA, as well as position 88 in ParC, appeared to be linked to increased resistance towards both quinolones included. As no notable differences in tertiary structure were observed between subunits of resistant and sensitive strains, the mechanism behind the observed resistance is likely due to subtle shifts in amino acid side chain properties.
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Turel, Iztok, Andrej Šonc, Marija Zupančič, Kristina Sepčić, and Tom Turk. "Biological Activity of Some Magnesium(II) Complexes of Quinolones." Metal-Based Drugs 7, no. 2 (January 1, 2000): 101–4. http://dx.doi.org/10.1155/mbd.2000.101.
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A new magnesium complex of quinolone antibacterial agent was prepared. This new complex as well as a previously isolated complex of magnesium with ciprofloxacin were tested against various Gram positive and Gram negative microorganisms. Antimicrobial activities were evaluated using the agar diffusion test. The results have shown that all magnesium complexes are significantly less active than the parent quinolone drugs. It was also found that the activity of quinolones is reduced when the solutions of quinolones are titrated with magnesium ions.
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Kenyon, Chris. "Positive Association between the Use of Quinolones in Food Animals and the Prevalence of Fluoroquinolone Resistance in E. coli and K. pneumoniae, A. baumannii and P. aeruginosa: A Global Ecological Analysis." Antibiotics 10, no. 10 (October 1, 2021): 1193. http://dx.doi.org/10.3390/antibiotics10101193.
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(1) Background: It is unclear what underpins the large global variations in the prevalence of fluoroquinolone resistance in Gram-negative bacteria. We tested the hypothesis that different intensities in the use of quinolones for food-animals play a role. (2) Methods: We used Spearman’s correlation to assess if the country-level prevalence of fluoroquinolone resistance in human infections with Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa was correlated with the use of quinolones for food producing animals. Linear regression was used to assess the relative contributions of country-level quinolone consumption for food-animals and humans on fluoroquinolone resistance in these 4 species. (3) Results: The prevalence of fluoroquinolone resistance in each species was positively associated with quinolone use for food-producing animals (E. coli [ρ = 0.55; p < 0.001], K. pneumoniae [ρ = 0.58; p < 0.001]; A. baumanii [ρ = 0.54; p = 0.004]; P. aeruginosa [ρ = 0.48; p = 0.008]). Linear regression revealed that both quinolone consumption in humans and food animals were independently associated with fluoroquinolone resistance in E. coli and A. baumanii. (4) Conclusions: Besides the prudent use of quinolones in humans, reducing quinolone use in food-producing animals may help retard the spread of fluoroquinolone resistance in various Gram-negative bacterial species.
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Barnard, Faye M., and Anthony Maxwell. "Interaction between DNA Gyrase and Quinolones: Effects of Alanine Mutations at GyrA Subunit Residues Ser83and Asp87." Antimicrobial Agents and Chemotherapy 45, no. 7 (July 1, 2001): 1994–2000. http://dx.doi.org/10.1128/aac.45.7.1994-2000.2001.
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ABSTRACT DNA gyrase is a target of quinolone antibacterial agents, but the molecular details of the quinolone-gyrase interaction are not clear. Quinolone resistance mutations frequently occur at residues Ser83 and Asp87 of the gyrase A subunit, suggesting that these residues are involved in drug binding. Single and double alanine substitutions were created at these positions (Ala83, Ala87, and Ala83Ala87), and the mutant proteins were assessed for DNA supercoiling, DNA cleavage, and resistance to a number of quinolone drugs. The Ala83 mutant was fully active in supercoiling, whereas the Ala87 and the double mutant were 2.5- and 4- to 5-fold less active, respectively; this loss in activity may be partly due to an increased affinity of these mutant proteins for DNA. Supercoiling inhibition and cleavage assays revealed that the double mutant has a high level of resistance to certain quinolones while the mutants with single alanine substitutions show low-level resistance. Using a drug-binding assay we demonstrated that the double-mutant enzyme-DNA complex has a lower affinity for ciprofloxacin than the wild-type complex. Based on the pattern of resistance to a series of quinolones, an interaction between the C-8 group of the quinolone and the double-mutant gyrase in the region of residues 83 and 87 is proposed.
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Strahilevitz, Jacob, George A. Jacoby, David C. Hooper, and Ari Robicsek. "Plasmid-Mediated Quinolone Resistance: a Multifaceted Threat." Clinical Microbiology Reviews 22, no. 4 (October 2009): 664–89. http://dx.doi.org/10.1128/cmr.00016-09.
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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.
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Yamada, H., S. Kurose-Hamada, Y. Fukuda, J. Mitsuyama, M. Takahata, S. Minami, Y. Watanabe, and H. Narita. "Quinolone susceptibility of norA-disrupted Staphylococcus aureus." Antimicrobial Agents and Chemotherapy 41, no. 10 (October 1997): 2308–9. http://dx.doi.org/10.1128/aac.41.10.2308.
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The MIC of norfloxacin for the norA-disrupted mutant termed RDN1, obtained from quinolone-susceptible Staphylococcus aureus RN4220, was eightfold lower than that for RN4220. The increase in susceptibility was related to an increase of drug accumulation by RDN1. These results indicate that NorA plays an important role in the susceptibility of quinolone-susceptible S. aureus to selected quinolones.
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Boyd, Derek R., Narain D. Sharma, Ludmila V. Modyanova, Jonathan G. Carroll, John F. Malone, Christopher CR Allen, John TG Hamilton, David T. Gibson, Rebecca E. Parales, and Howard Dalton. "Dioxygenase-catalyzed cis-dihydroxylation of pyridine-ring systems." Canadian Journal of Chemistry 80, no. 6 (June 1, 2002): 589–600. http://dx.doi.org/10.1139/v02-062.
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Toluene dioxygenase-catalyzed dihydroxylation, in the carbocyclic rings of quinoline, 2-chloroquinoline, 2-methoxyquinoline, and 3-bromoquinoline, was found to yield the corresponding enantiopure cis-5,6- and -7,8-dihy dro diol metabolites using whole cells of Pseudomonas putida UV4. cis-Dihydroxylation at the 3,4-bond of 2-chloroquino line, 2-methoxyquinoline, and 2-quinolone was also found to yield the heterocyclic cis-dihydrodiol metabolite, (+)-cis-(3S,4S)-3,4-dihydroxy-3,4-dihydro-2-quinolone. Heterocyclic cis-dihydrodiol metabolites, resulting from dihydroxylation at the 5,6- and 3,4-bonds of 1-methyl 2-pyridone, were isolated from bacteria containing toluene, naphthalene, and biphenyl dioxygenases. The enantiomeric excess (ee) values (>98%) and the absolute configurations of the carbocyclic cis-dihydrodiol metabolites of quinoline substrates (benzylic R) and of the heterocyclic cis-diols from quinoline, 2-quinolone, and 2-pyridone substrates (allylic S) were found to be in accord with earlier models for dioxygenase-catalyzed cis-dihydroxylation of carbocyclic arenes. Evidence favouring the dioxygenase-catalyzed cis-dihydroxylation of pyridine-ring systems is presented.Key words: dioxygenases; cis-dihydroxylation, pyridines, 2-pyridones, absolute configurations.
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Ata, Zafer, Artun Yibar, Erdem Arslan, Kaan Mustak, and Elcin Gunaydin. "Plasmid-mediated quinolone resistance in Salmonella serotypes isolated from chicken carcasses in Turkey." Acta Veterinaria Brno 83, no. 4 (2014): 281–86. http://dx.doi.org/10.2754/avb201483040281.
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Quinolones have been extensively used for treatment of a variety of invasive and systemic infections of salmonellosis. Widespread use of these agents has been associated with the emergence and dissemination of quinolone-resistant pathogens. The quinolone resistance and plasmid-mediated quinolone resistance determinants (qnrA, qnrB, qnrS and aac(6’)-Ib-cr) of 85 Salmonella isolates from chicken carcasses were investigated in this study. Isolates were serotyped according to the Kauffman-White-Le Minor scheme, and broth microdilution method was used to determine quinolone resistance. Plasmid-mediated quinolone resistance genes were investigated by real-time PCR and positive results were confirmed by sequencing. Among the Salmonella isolates, 30/85 (35%) and 18/85 (21%) were found to be resistant to enrofloxacin (MIC ≥ 2 mg/ml), and danofloxacin (MIC ≥ 2 mg/ml), respectively. All the isolates were negative for qnrA, qnrB and aac(6’)-Ib-cr genes, nevertheless 2% (S. Brandenburg and S. Dabou) were positive for qnrS (qnrS1 determinant). This study is the first and unique investigating the plasmid- mediated quinolone resistance determinants of Salmonella isolated from chicken carcasses in Turkey.
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Leski, Tomasz A., Michael G. Stockelman, Umaru Bangura, Daniel Chae, Rashid Ansumana, David A. Stenger, Gary J. Vora, and Chris R. Taitt. "Prevalence of Quinolone Resistance in Enterobacteriaceae from Sierra Leone and the Detection ofqnrBPseudogenes and Modified LexA Binding Sites." Antimicrobial Agents and Chemotherapy 60, no. 11 (August 29, 2016): 6920–23. http://dx.doi.org/10.1128/aac.01576-16.
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ABSTRACTA collection of 74Enterobacteriaceaeisolates found in Bo, Sierra Leone, were tested for quinolone antibiotic susceptibility and resistance mechanisms. The majority of isolates (62%) were resistant to quinolones, and 61% harbored chromosomalgyrAand/orparCmutations. Plasmid-mediated quinolone resistance genes were ubiquitous, withqnrBandaac(6′)-Ib-crbeing the most prevalent. Mutated LexA binding sites were found in allqnrB1genes, and truncatedqnrBpseudogenes were found in the majority ofCitrobacterisolates.
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S. El-Kazzaz, Samah, and Noha M. Mahmoud. "Virulence Factors Associated with Quinolone Resistance in Proteus Species Isolated from Patients with Urinary Tract Infection." EJMM-Volume 30-Issue 1 30, no. 1 (January 1, 2021): 115–23. http://dx.doi.org/10.51429/ejmm30115.
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Background: Proteus is an important causative organism of urinary system infections. The invasive nature of Proteus is supported by expression of multiple virulence factors; the infection outcome gets worse when those virulent isolates acquire antibiotic resistant determinants. Objectives: The present study was aiming at isolation of Proteus from urine of patients with urinary tract infections (UTIs) and to assess the relation between virulence factors expression and presence of quinolones resistance genes in those isolates. Methodology: Quinolone resistant Proteus isolates were chosen for detection of quinolone resistance genes, also they were tested for presence of different virulence factors. Results: Sixty eight quinolone resistant Proteus isolates were determined. aac(6′)- Ib-cr was the most frequently detected quinolone resistance gene. Haemagglutination, haemolytic activity, protease production and biofilm formation were documented in 79.4%, 76.5%, 70.6% and 83.8% of the isolates respectively. Conclusion: Proteus isolated from urine displayed many virulence factors and harbored a variety of quinolone resistance genes.
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Ma, Xiaoping, Bowen Zheng, Jiafan Wang, Gen Li, Sanjie Cao, Yiping Wen, Xiaobo Huang, Zhicai Zuo, Zhijun Zhong, and Yu Gu. "Quinolone Resistance of Actinobacillus pleuropneumoniae Revealed through Genome and Transcriptome Analyses." International Journal of Molecular Sciences 22, no. 18 (September 17, 2021): 10036. http://dx.doi.org/10.3390/ijms221810036.
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Actinobacillus pleuropneumoniae is a pathogen that infects pigs and poses a serious threat to the pig industry. The emergence of quinolone-resistant strains of A.pleuropneumoniae further limits the choice of treatment. However, the mechanisms behind quinolone resistance in A.pleuropneumoniae remain unclear. The genomes of a ciprofloxacin-resistant strain, A. pleuropneumoniae SC1810 and its isogenic drug-sensitive counterpart were sequenced and analyzed using various bioinformatics tools, revealing 559 differentially expressed genes. The biological membrane, plasmid-mediated quinolone resistance genes and quinolone resistance-determining region were detected. Upregulated expression of efflux pump genes led to ciprofloxacin resistance. The expression of two porins, OmpP2B and LamB, was significantly downregulated in the mutant. Three nonsynonymous mutations in the mutant strain disrupted the water–metal ion bridge, subsequently reducing the affinity of the quinolone–enzyme complex for metal ions and leading to cross-resistance to multiple quinolones. The mechanism of quinolone resistance in A. pleuropneumoniae may involve inhibition of expression of the outer membrane protein genes ompP2B and lamB to decrease drug influx, overexpression of AcrB in the efflux pump to enhance its drug-pumping ability, and mutation in the quinolone resistance-determining region to weaken the binding of the remaining drugs. These findings will provide new potential targets for treatment.
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Disratthakit, Areeya, Therdsak Prammananan, Chanwit Tribuddharat, Iyarit Thaipisuttikul, Norio Doi, Manoon Leechawengwongs, and Angkana Chaiprasert. "Role ofgyrBMutations in Pre-extensively and Extensively Drug-Resistant Tuberculosis in Thai Clinical Isolates." Antimicrobial Agents and Chemotherapy 60, no. 9 (June 13, 2016): 5189–97. http://dx.doi.org/10.1128/aac.00539-16.
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ABSTRACTDNA gyrase mutations are a major cause of quinolone resistance inMycobacterium tuberculosis. We therefore conducted the first comprehensive study to determine the diversity of gyrase mutations in pre-extensively drug-resistant (pre-XDR) (n= 71) and extensively drug-resistant (XDR) (n= 30) Thai clinical tuberculosis (TB) isolates. All pre-XDR-TB and XDR-TB isolates carried at least one mutation within the quinolone resistance-determining region of GyrA (G88A [1.1%], A90V [17.4%], S91P [1.1%], or D94A/G/H/N/V/Y [72.7%]) or GyrB (D533A [1.1%], N538D [1.1%], or E540D [2.2%]). MIC and DNA gyrase supercoiling inhibition assays were performed to determine the role of gyrase mutations in quinolone resistance. Compared to the MICs againstM. tuberculosisH37Rv, the levels of resistance to all quinolones tested in the isolates that carried GyrA-D94G or GyrB-N538D (8- to 32-fold increase) were significantly higher than those in isolates bearing GyrA-D94A or GyrA-A90V (2- to 8-fold increase) (P< 0.01). Intriguingly, GyrB-E540D led to a dramatic resistance to later-generation quinolones, including moxifloxacin, gatifloxacin, and sparfloxacin (8- to 16-fold increases in MICs and 8.3- to 11.2-fold increases in 50% inhibitory concentrations [IC50s]). However, GyrB-E540D caused low-level resistance to early-generation quinolones, including ofloxacin, levofloxacin, and ciprofloxacin (2- to 4-fold increases in MICs and 1.5- to 2.0-fold increases in IC50s). In the present study, DC-159a was the most active antituberculosis agent and was little affected by the gyrase mutations described above. Our findings suggest that although they are rare,gyrBmutations have a notable role in quinolone resistance, which may provide clues to the molecular basis of estimating quinolone resistance levels for drug and dose selection.
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Hayashi, Norihiro, Yoshihiro Nakata, and Akira Yazaki. "New Findings on the Structure-Phototoxicity Relationship and Photostability of Fluoroquinolones with Various Substituents at Position 1." Antimicrobial Agents and Chemotherapy 48, no. 3 (March 2004): 799–803. http://dx.doi.org/10.1128/aac.48.3.799-803.2004.
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ABSTRACT The present study examined the phototoxicities of a series of 7-(3-aminopyrrolidinyl) quinolones containing various substituents at position 1 (in which the substituent at R8 is a hydrogen or a halogen) by use of a mouse model. For the 7-(3-aminopyrrolidinyl) quinolones with a halogen atom at position 8, well-known substituent groups such as a cyclopropyl, an ethyl, or a difluorophenyl at position 1 were found to be responsible for severe phototoxicity. However, when an aminodifluorophenyl or an isoxazolyl group was placed at position 1, even 8-halogeno quinolones were found to be mildly phototoxic. This is the first report of 8-halogeno quinolones that are not severely phototoxic. Two structurally similar 8-chloro quinolones (the 1-aminodifluorophenyl 8-chloro quinolone and the 1-difluorophenyl 8-chloro quinolone) were investigated further. The former was mildly phototoxic; the latter was severely phototoxic. We demonstrate that these two 8-chloro quinolones have practically the same areas under the concentration-time curves from 0 to 4 h in auricular tissue, suggesting that the mild phototoxicity is not due to pharmacokinetic instability. The rates of UV photodegradation of these compounds were also measured. We found that these two quinolones photodegrade at similar rates, suggesting that the mild phototoxicity is not attained through increased photostability. In conclusion, the phototoxic potentials of fluoroquinolones are influenced not only by the substituent at position 8 but also by that at position 1 (a new finding from this study). We also discovered a mildly phototoxic 8-chloro quinolone which did not have increased photostability.
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Uda, Atsushi, Katsumi Shigemura, Koichi Kitagawa, Kayo Osawa, Mari Kusuki, Yonmin Yan, Ikuko Yano, and Takayuki Miyara. "Effect of Antimicrobial Stewardship on Oral Quinolone Use and Resistance Patterns over 8 Years (2013–2020)." Antibiotics 10, no. 11 (November 22, 2021): 1426. http://dx.doi.org/10.3390/antibiotics10111426.
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Since 2014, several global and national guidelines have been introduced to address the problem of antimicrobial resistance. We conducted a campaign in a tertiary hospital to promote appropriate quinolone use through educational lectures in 2018. The aim of this retrospective study was to evaluate the changes in the following: prescription characteristics, trend of oral quinolone use, and antibiotic susceptibility of bacteria from 2013 to 2020. Antimicrobial use was assessed as days of therapy per 1000 patient-days. We found a significant reduction in unnecessary antibiotic prescriptions between December 2013 and December 2020. Significant negative trends were detected in the use of quinolones over 8 years (outpatients, coefficient = −0.15655, p < 0.001; inpatients, coefficient = −0.004825, p = 0.0016). In particular, the monthly mean use of quinolones among outpatients significantly decreased by 11% from 2013 to 2014 (p < 0.05) and reduced further by 31% from 2017 to 2020 (p < 0.001). A significant positive trend was observed in the susceptibility of Pseudomonas aeruginosa to levofloxacin (p < 0.001). These results demonstrate that the use of oral quinolones was further reduced following educational intervention and the bacterial susceptibility improved with optimal quinolone usage compared to that in 2013.
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Chuah, Seng-Kee, Wei-Chen Tai, Chen-Hsiang Lee, Chih-Ming Liang, and Tsung-Hui Hu. "Quinolone-Containing Therapies in the Eradication ofHelicobacter pylori." BioMed Research International 2014 (2014): 1–5. http://dx.doi.org/10.1155/2014/151543.
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Fluoroquinolones, especially levofloxacin, are used in the eradication ofHelicobacter pyloriworldwide. Many consensus guidelines recommend that the second-line rescue therapy forH. pylorieradication consists of a proton pump inhibitor, a quinolone, and amoxicillin as an option. Unfortunately, quinolone is well associated with a risk of developing bacterial resistance. In this paper, we review quinolone-containingH. pylorieradication regimens and the challenges that influence the efficacy of eradication. It is generally suggested that the use of levofloxacin should be confined to “rescue” therapy only, in order to avoid a further rapid increase in the resistance ofH. pylorito quinolone. The impact of quinolone-containingH. pylorieradication regimens on public health issues such as tuberculosis treatment must always be taken into account. Exposure to quinolone is relevant to delays in diagnosing tuberculosis and the development of drug resistance. Extending the duration of treatment to 14 days improves eradication rates by >90%. Tailored therapy to detect fluoroquinolone-resistant strains can be done by culture-based and molecular methods to provide better eradication rates. Molecular methods are achieved by using a real-time polymerase chain reaction to detect the presence of agyrAmutation, which is predictive of treatment failure with quinolones-containing triple therapy.
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Abdel-Rhman, Shaymaa H., Rehab M. Elbargisy, and Dina E. Rizk. "Characterization of Integrons and Quinolone Resistance in Clinical Escherichia coli Isolates in Mansoura City, Egypt." International Journal of Microbiology 2021 (September 4, 2021): 1–11. http://dx.doi.org/10.1155/2021/6468942.
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Escherichia coli is a common pathogen in both humans and animals. Quinolones are used to treat infections caused by Gram-negative bacteria, but resistance genes emerged. Only scarce studies investigated the association between plasmid-mediated quinolone resistance (PMQR) genes and integrons in clinical isolates of E. coli. The current study investigated the prevalence of quinolone resistance and integrons among 134 clinical E. coli isolates. Eighty (59.70%) isolates were quinolone-resistant, and 60/134 (44.77%) isolates were integron positive with the predominance of class I integrons (98.33%). There was a significant association between quinolone resistance and the presence of integrons ( P < 0.0001 ). Isolates from Urology and Nephrology Center and Gastroenterology Hospital were significantly quinolone-resistant and integron positive ( P ≤ 0.0005 ). Detection of PMQR genes on plasmids of integron-positive isolates showed that the active efflux pump genes oqxAB and qepA had the highest prevalence (72.22%), followed by the aminoglycoside acetyltransferase gene (aac(6′)-Ib-cr, 66.67%) and the quinolone resistance genes (qnr, 61.11%). Amplification and sequencing of integrons’ variable regions illustrated that no quinolone resistance genes were detected, and the most predominant gene cassettes were for trimethoprim and aminoglycoside resistance including dfrA17, dfrB4, and dfrA17-aadA5. In conclusion, this study reported the high prevalence of PMQR genes and integrons among clinical E. coli isolates. Although PMQR genes are not cassette-born, they were associated with integrons’ presence, which contributes to the widespread of quinolone resistance in Egypt.
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Browne, Frederick A., Bülent Bozdogan, Catherine Clark, Linda M. Kelly, Lois Ednie, Klaudia Kosowska, Bonifacio Dewasse, Michael R. Jacobs, and Peter C. Appelbaum. "Antipneumococcal Activity of DK-507k, a New Quinolone, Compared with the Activities of 10 Other Agents." Antimicrobial Agents and Chemotherapy 47, no. 12 (December 2003): 3815–24. http://dx.doi.org/10.1128/aac.47.12.3815-3824.2003.
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ABSTRACT 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 μg/ml, respectively), followed by moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. MICs of β-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 μg/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.
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Clark, Catherine, Kathy Smith, Lois Ednie, Tatiana Bogdanovich, Bonifacio Dewasse, Pamela McGhee, and Peter C. Appelbaum. "In Vitro Activity of DC-159a, a New Broad-Spectrum Fluoroquinolone, Compared with That of Other Agents against Drug-Susceptible and -Resistant Pneumococci." Antimicrobial Agents and Chemotherapy 52, no. 1 (October 15, 2007): 77–84. http://dx.doi.org/10.1128/aac.01229-07.
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ABSTRACT DC-159a yielded MICs of ≤1 μg/ml against 316 strains of both quinolone-susceptible and -resistant pneumococci (resistance was defined as a levofloxacin MIC ≥4 μg/ml). Although the MICs for DC-159a against quinolone-susceptible pneumococci were a few dilutions higher than those of gemifloxacin, the MICs of these two compounds against 28 quinolone-resistant pneumococci were identical. The DC-159a MICs against quinolone-resistant strains did not appear to depend on the number or the type of mutations in the quinolone resistance-determining region. DC-159a, as well as the other quinolones tested, was bactericidal after 24 h at 2× MIC against 11 of 12 strains tested. Two of the strains were additionally tested at 1 and 2 h, and DC-159a at 4× MIC showed significant killing as early as 2 h. Multistep resistance selection studies showed that even after 50 consecutive subcultures of 10 strains in the presence of sub-MICs, DC-159a produced only two mutants with maximum MICs of 1 μg/ml.
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Aldred, Katie J., Erin J. Breland, Sylvia A. McPherson, Charles L. Turnbough, Robert J. Kerns, and Neil Osheroff. "Bacillus anthracis GrlAV96ATopoisomerase IV, a Quinolone Resistance Mutation That Does Not Affect the Water-Metal Ion Bridge." Antimicrobial Agents and Chemotherapy 58, no. 12 (September 22, 2014): 7182–87. http://dx.doi.org/10.1128/aac.03734-14.
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ABSTRACTThe rise in quinolone resistance is threatening the clinical use of this important class of broad-spectrum antibacterials. Quinolones kill bacteria by increasing the level of DNA strand breaks generated by the type II topoisomerases gyrase and topoisomerase IV. Most commonly, resistance is caused by mutations in the serine and acidic amino acid residues that anchor a water-metal ion bridge that facilitates quinolone-enzyme interactions. Although other mutations in gyrase and topoisomerase IV have been reported in quinolone-resistant strains, little is known regarding their contributions to cellular quinolone resistance. To address this issue, we characterized the effects of the V96A mutation in the A subunit ofBacillus anthracistopoisomerase IV on quinolone activity. The results indicate that this mutation causes an ∼3-fold decrease in quinolone potency and reduces the stability of covalent topoisomerase IV-cleaved DNA complexes. However, based on metal ion usage, the V96A mutation does not disrupt the function of the water-metal ion bridge. A similar level of resistance to quinazolinediones (which do not use the bridge) was seen. V96A is the first topoisomerase IV mutation distal to the water-metal ion bridge demonstrated to decrease quinolone activity. It also represents the first A subunit mutation reported to cause resistance to quinazolinediones. This cross-resistance suggests that the V96A change has a global effect on the structure of the drug-binding pocket of topoisomerase IV.