ArticleAntimicrobial agents and chemotherapy2005
Dual targeting of topoisomerase IV and gyrase to reduce mutant selection: direct testing of the paradigm by using WCK-1734, a new fluoroquinolone, and ciprofloxacin.
Article in Antimicrobial agents and chemotherapy, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed.
- A Review of Fluoroquinolones with a Focus on Veterinary-Approved Agents.Biomolecules · 2026Review
- Mechanism of Action of Gepotidacin: Well-Balanced Dual-Targeting againstACS infectious diseases · 2025Article
- Pradofloxacin Minimum Inhibitory Concentration Profiling ofPathogens (Basel, Switzerland) · 2025Article
- Comparison of the Minimum Inhibitory and Mutant Prevention Drug Concentrations for Pradofloxacin and 7 Other Antimicrobial Agents Tested Against Swine Isolates ofMolecules (Basel, Switzerland) · 2024Article
- Updated Review on Clinically-Relevant Properties of Delafloxacin.Antibiotics (Basel, Switzerland) · 2023Review
- Discovery of Quinazoline-2,4(1Molecules (Basel, Switzerland) · 2022Article
- What makes a type IIA topoisomerase a gyrase or a Topo IV?Nucleic acids research · 2021Review
- Genomics accurately predicts antimicrobial resistance in Staphylococcus pseudintermedius collected as part of Vet-LIRN resistance monitoring.Veterinary microbiology · 2021Article
- Towards Conformation-Sensitive Inhibition of Gyrase: Implications of Mechanistic Insight for the Identification and Improvement of Inhibitors.Molecules (Basel, Switzerland) · 2021Review
- Article
- Topoisomerases as anticancer targets.The Biochemical journal · 2018Review
- Targeting Multiple Aminoacyl-tRNA Synthetases Overcomes the Resistance Liabilities Associated with Antibacterial Inhibitors Acting on a Single Such Enzyme.Antimicrobial agents and chemotherapy · 2016Article
- Topoisomerase Inhibitors: Fluoroquinolone Mechanisms of Action and Resistance.Cold Spring Harbor perspectives in medicine · 2016Review
- The population genetics of drug resistance evolution in natural populations of viral, bacterial and eukaryotic pathogens.Molecular ecology · 2016Review
- Mechanisms of drug resistance: quinolone resistance.Annals of the New York Academy of Sciences · 2015Review
- Target-based resistance in Pseudomonas aeruginosa and Escherichia coli to NBTI 5463, a novel bacterial type II topoisomerase inhibitor.Antimicrobial agents and chemotherapy · 2015Article
- Bioactive nanofibrous scaffolds for regenerative endodontics.Journal of dental research · 2013Article
- Antistaphylococcal activities of the new fluoroquinolone JNJ-Q2.Antimicrobial agents and chemotherapy · 2011Article
- Challenges of antibacterial discovery.Clinical microbiology reviews · 2011Review
- Comparison of in vitro activities of fluoroquinolone-like 2,4- and 1,3-diones.Antimicrobial agents and chemotherapy · 2010Article
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2 authors.
Funding
Abstract
Quinolones that act equally against DNA gyrase and topoisomerase IV are a desirable modality to decrease the selection of resistant strains. We first determined by genetic and biochemical studies in Staphylococcus aureus that the primary target enzyme of WCK-1734, a new quinolone, was DNA gyrase. A single mutation in gyrase, but not topoisomerase IV, caused a two- to fourfold increase in the MIC. Studies with purified topoisomerase IV and gyrase from S. aureus also showed that gyrase was more sensitive than topoisomerase IV to WCK-1734 (50% inhibitory concentration, 1.25 and 2.5 to 5.0 microg/ml, respectively; 50% stimulation of cleavage complex formation, 0.62 and 2.5 to 5.0 microg/ml, respectively). To test the effect of balanced activity of quinolones against the two target enzymes, we measured the frequency of selection of mutants with ciprofloxacin (which targets topoisomerase IV) and WCK-1734 alone and in combination. With the combination of ciprofloxacin and WCK-1734, each at its MIC, the ratio of frequency of mutants selected was significantly lower than that with each drug alone at two times their respective MICs. We further characterized resistant strains selected with the combination of ciprofloxacin and WCK-1734 and found evidence to suggest the existence of novel mutational mechanisms for low-level quinolone resistance. By use of a combination of differentially targeting quinolones, this study provides novel data in direct support of the paradigm for dual targeting of quinolone action and reduced development of resistance.
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