ArticleAntimicrobial agents and chemotherapy2011
Fluoroquinolone and quinazolinedione activities against wild-type and gyrase mutant strains of Mycobacterium smegmatis.
Article in Antimicrobial agents and chemotherapy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 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
- Target-Mediated Fluoroquinolone Resistance inACS infectious diseases · 2024Article
- Synthesis of 3-(Pyridin-2-yl)quinazolin-2,4(1International journal of molecular sciences · 2023Article
- Role of the Water-Metal Ion Bridge in Quinolone Interactions withInternational journal of molecular sciences · 2023Article
- Discovery of Quinazoline-2,4(1Molecules (Basel, Switzerland) · 2022Article
- A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA.Cell chemical biology · 2020Article
- SOS Response Inhibitory Properties by Potential Probiotic Formulations of Bacillus amyloliquefaciens B-1895 and Bacillus subtilis KATMIRA1933 Obtained by Solid-State Fermentation.Current microbiology · 2019Article
- The Use of Biosensors to Explore the Potential of Probiotic Strains to Reduce the SOS Response and Mutagenesis in Bacteria.Biosensors · 2018Article
- Ubiquitous Nature of Fluoroquinolones: The Oscillation between Antibacterial and Anticancer Activities.Antibiotics (Basel, Switzerland) · 2017Review
- Synthesis of new quinazolin-2,4-diones as anti-Leishmania mexicana agents.Molecular diversity · 2016Article
- Suppression of gyrase-mediated resistance by C7 aryl fluoroquinolones.Nucleic acids research · 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
- Bacillus anthracis GrlAV96A topoisomerase IV, a quinolone resistance mutation that does not affect the water-metal ion bridge.Antimicrobial agents and chemotherapy · 2014Article
- Role of the water-metal ion bridge in mediating interactions between quinolones and Escherichia coli topoisomerase IV.Biochemistry · 2014Article
- Fluoroquinolone-gyrase-DNA complexes: two modes of drug binding.The Journal of biological chemistry · 2014Article
- Mechanism of quinolone action and resistance.Biochemistry · 2014Review
Corrections and comments
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Authors and funding
7 authors.
Funding
Abstract
Quinazolinediones (diones) are fluoroquinolone-like inhibitors of bacterial gyrase and DNA topoisomerase IV. To assess activity against mycobacteria, C-8-methoxy dione derivatives were compared with cognate fluoroquinolones by using cultured Mycobacterium smegmatis. Diones exhibited higher MIC values than fluoroquinolones; however, MICs for fluoroquinolone-resistant gyrA mutants, normalized to the MIC for wild-type cells, were lower. Addition of a 3-amino group to the 2,4-dione core increased relative activity against mutants, while alteration of the 8-methoxy group to a methyl or of the 2,4-dione core to a 1,3-dione core lowered activity against mutants. A GyrA G89C bacterial variant was strikingly susceptible to most of the diones tested; in contrast, low susceptibility to fluoroquinolones was observed. Many of the bacteriostatic differences between diones and fluoroquinolones were explained by interactions at the N terminus of GyrA helix IV revealed by recently published X-ray structures of drug-topoisomerase-DNA complexes. When lethal activity was normalized to the MIC in order to minimize the effects of drug uptake, efflux, and ternary complex formation, a 3-amino-2,4-dione exhibited killing activity comparable to that of a cognate fluoroquinolone. Surprisingly, the lethal activity of the dione was inhibited less by chloramphenicol than that of the cognate fluoroquinolone. This observation adds the 2,4-dione structural motif to the list of structural features known to impart lethality to fluoroquinolone-like compounds in the absence of protein synthesis, a phenomenon that is not explained by X-ray structures of drug-enzyme-DNA complexes.
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