ArticleAntimicrobial agents and chemotherapy2008
Use of gyrase resistance mutants to guide selection of 8-methoxy-quinazoline-2,4-diones.
Article in Antimicrobial agents and chemotherapy, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed.
- A Comprehensive Review on Discovery, Development, the Chemistry of Quinolones, and Their Antimicrobial Resistance.Current topics in medicinal chemistry · 2026Review
- Quinazoline-2,4(1H,3H)-dione derivatives as new class of CB1 Agonists: A pharmacophore-based virtual screening workflow and drug discovery.F1000Research · 2025Article
- Navigating fluoroquinolone resistance in Gram-negative bacteria: a comprehensive evaluation.JAC-antimicrobial resistance · 2024Review
- Target-Mediated Fluoroquinolone Resistance inACS infectious diseases · 2024Article
- Discovery of Quinazoline-2,4(1Molecules (Basel, Switzerland) · 2022Article
- New marine-derived indolymethyl pyrazinoquinazoline alkaloids with promising antimicrobial profiles.RSC advances · 2020Article
- Quinolone antibiotics.MedChemComm · 2019Review
- Article
- Novel N-1 substituted fluoroquinolones inhibit human topoisomerase I activity and exhibit anti-proliferative activity.Investigational new drugs · 2019Article
- A new class of antibacterials, the imidazopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance.Nucleic acids research · 2018Article
- Suppression of gyrase-mediated resistance by C7 aryl fluoroquinolones.Nucleic acids research · 2016Article
- Fluoroquinolones stimulate the DNA cleavage activity of topoisomerase IV by promoting the binding of Mg(2+) to the second metal binding site.Biochimica et biophysica acta · 2016Article
- Crystal structure and stability of gyrase-fluoroquinolone cleaved complexes from Mycobacterium tuberculosis.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Fluoroquinolone interactions with Mycobacterium tuberculosis gyrase: Enhancing drug activity against wild-type and resistant gyrase.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Activity of quinolone CP-115,955 against bacterial and human type II topoisomerases is mediated by different interactions.Biochemistry · 2015Article
- Bypassing fluoroquinolone resistance with quinazolinediones: studies of drug-gyrase-DNA complexes having implications for drug design.ACS chemical biology · 2014Article
- Role of the water-metal ion bridge in mediating interactions between quinolones and Escherichia coli topoisomerase IV.Biochemistry · 2014Article
- Mechanism of quinolone action and resistance.Biochemistry · 2014Review
- Overcoming target-mediated quinolone resistance in topoisomerase IV by introducing metal-ion-independent drug-enzyme interactions.ACS chemical biology · 2013Article
- Topoisomerase IV-quinolone interactions are mediated through a water-metal ion bridge: mechanistic basis of quinolone resistance.Nucleic acids research · 2013Article
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5 authors.
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Abstract
A series of 1-cyclopropyl-8-methoxy-quinazoline-2,4-diones was synthesized and evaluated for lowering the ratio of the antimicrobial MIC in gyrase resistance mutants to that in the gyr(+) (wild type) using isogenic strains of Escherichia coli. Dione features that lowered this ratio were a 3-amino group and C-7 ring structure (3-aminomethyl pyrrolidinyl < 3-aminopyrrolidinyl < diazobicyclo < 2-ethyl piperazinyl). The wild-type MIC was also lowered. With the most active derivative tested, many gyrA resistance mutant types were as susceptible as, or more susceptible than, wild-type cells. The most active 2,4-dione derivatives were also more active with two quinolone-resistant gyrB mutants than with wild-type cells. With respect to lethality, the most bacteriostatic 2,4-dione killed E. coli at a rate that was affected little by a gyrA resistance mutation, and it exhibited a rate of killing similar to its cognate fluoroquinolone at 10x the MIC. Population analysis with wild-type E. coli applied to agar showed that the mutant selection window for the most active 2,4-dione was narrower than that for the cognate fluoroquinolone or for ciprofloxacin. These data illustrate a new approach to guide early-stage antimicrobial selection. Use of antimutant activity (i.e., ratio of the antimicrobial MIC in a mutant strain to the antimicrobial MIC in a wild-type strain) as a structure-function selection criterion can be combined with traditional efforts aimed at lowering antimicrobial MICs against wild-type organisms to more effectively afford lead molecules with activity against both wild-type and mutant cells.
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