ArticleAntimicrobial agents and chemotherapy2002
Dual targeting of DNA gyrase and topoisomerase IV: target interactions of garenoxacin (BMS-284756, T-3811ME), a new desfluoroquinolone.
Article in Antimicrobial agents and chemotherapy, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31 citing papers in PubMed, 78 citations in OpenAlex.
- Klebsiella pneumoniae in the global AMR: resistance mechanisms and genomic adaptation.World journal of microbiology & biotechnology · 2026Review
- A Comprehensive Review on Discovery, Development, the Chemistry of Quinolones, and Their Antimicrobial Resistance.Current topics in medicinal chemistry · 2026Review
- Efflux pump gene amplifications bypass necessity of multiple target mutations for resistance against dual-targeting antibiotic.Nature communications · 2023Article
- The Effect of Conjugation of Ciprofloxacin and Moxifloxacin with Fatty Acids on Their Antibacterial and Anticancer Activity.International journal of molecular sciences · 2022Article
- Biological Effects of Quinolones: A Family of Broad-Spectrum Antimicrobial Agents.Molecules (Basel, Switzerland) · 2021Review
- Article
- Topoisomerases as anticancer targets.The Biochemical journal · 2018Review
- Antibiotic adjuvants: diverse strategies for controlling drug-resistant pathogens.Chemical biology & drug design · 2015Article
- Target-based resistance in Pseudomonas aeruginosa and Escherichia coli to NBTI 5463, a novel bacterial type II topoisomerase inhibitor.Antimicrobial agents and chemotherapy · 2015Article
- Comparison of in vitro activities of fluoroquinolone-like 2,4- and 1,3-diones.Antimicrobial agents and chemotherapy · 2010Article
- Efficient Synthesis of the 2-amino-6-chloro-4-cyclopropyl-7-fluoro-5-methoxy-pyrido[1,2-c]pyrimidine-1,3-dione core ring system.Tetrahedron letters · 2009Article
- Quinolones: action and resistance updated.Current topics in medicinal chemistry · 2009Review
- Use of gyrase resistance mutants to guide selection of 8-methoxy-quinazoline-2,4-diones.Antimicrobial agents and chemotherapy · 2008Article
- Mechanism of action of the antibiotic NXL101, a novel nonfluoroquinolone inhibitor of bacterial type II topoisomerases.Antimicrobial agents and chemotherapy · 2008Article
- In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: studies of the mode of action in Staphylococcus aureus.Antimicrobial agents and chemotherapy · 2008Article
- Dual targeting of GyrB and ParE by a novel aminobenzimidazole class of antibacterial compounds.Antimicrobial agents and chemotherapy · 2007Article
- The anti-methicillin-resistant Staphylococcus aureus quinolone WCK 771 has potent activity against sequentially selected mutants, has a narrow mutant selection window against quinolone-resistant Staphylococcus aureus, and preferentially targets DNA gyrase.Antimicrobial agents and chemotherapy · 2006Article
- Role of the extended alpha4 domain of Staphylococcus aureus gyrase A protein in determining low sensitivity to quinolones.Antimicrobial agents and chemotherapy · 2006Article
- DX-619, a novel des-fluoro(6) quinolone manifesting low frequency of selection of resistant Staphylococcus aureus mutants: quinolone resistance beyond modification of type II topoisomerases.Antimicrobial agents and chemotherapy · 2005Article
- Novel Ser79Leu and Ser81Ile substitutions in the quinolone resistance-determining regions of ParC topoisomerase IV and GyrA DNA gyrase subunits from recent fluoroquinolone-resistant Streptococcus pneumoniae clinical isolates.Antimicrobial agents and chemotherapy · 2005Article
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4 authors at 2 institutions in 1 country.
Funding
Abstract
We determined the target enzyme interactions of garenoxacin (BMS-284756, T-3811ME), a novel desfluoroquinolone, in Staphylococcus aureus by genetic and biochemical studies. We found garenoxacin to be four- to eightfold more active than ciprofloxacin against wild-type S. aureus. A single topoisomerase IV or gyrase mutation caused only a 2- to 4-fold increase in the MIC of garenoxacin, whereas a combination of mutations in both loci caused a substantial increase (128-fold). Overexpression of the NorA efflux pump had minimal effect on resistance to garenoxacin. With garenoxacin at twice the MIC, selection of resistant mutants (<7.4 x 10(-12) to 4.0 x 10(-11)) was 5 to 6 log units less than that with ciprofloxacin. Mutations inside or outside the quinolone resistance-determining regions (QRDR) of either topoisomerase IV, or gyrase, or both were selected in single-step mutants, suggesting dual targeting of topoisomerase IV and gyrase. Three of the novel mutations were shown by genetic experiments to be responsible for resistance. Studies with purified topoisomerase IV and gyrase from S. aureus also showed that garenoxacin had similar activity against topoisomerase IV and gyrase (50% inhibitory concentration, 1.25 to 2.5 and 1.25 micro g/ml, respectively), and although its activity against topoisomerase IV was 2-fold greater than that of ciprofloxacin, its activity against gyrase was 10-fold greater. This study provides the first genetic and biochemical data supporting the dual targeting of topoisomerase IV and gyrase in S. aureus by a quinolone as well as providing genetic proof for the expansion of the QRDRs to include the 5' terminus of grlB and the 3' terminus of gyrA.
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