ArticleProceedings of the National Academy of Sciences of the United States of America2016
Fluoroquinolone interactions with Mycobacterium tuberculosis gyrase: Enhancing drug activity against wild-type and resistant gyrase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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61 citing papers in PubMed, 100 citations in OpenAlex.
- Computational introspection of impact of mutation A90V and A90E in DNA gyrase a of Mycobacterium tuberculosis in developing resistance against Delafloxacin.Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology] · 2026Article
- Bacterial type II topoisomerases cleave DNA in a species-specific manner.Nucleic acids research · 2026Article
- Real-World Assessment of the Xpert MTB/XDR for Detecting Isoniazid and Second-Line Drug Resistance Among TB Patients.International journal of molecular sciences · 2026Article
- Enzyme-DNA Interactions Affect the Catalytic Inhibition of Mycobacterial Gyrases by Antibacterial Drugs.ACS infectious diseases · 2026Article
- Bovine Mastitis Therapy at a Crossroads: Pharmacokinetic Barriers, Biofilms, Antimicrobial Resistance, and Emerging Solutions.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Direct trapping of the transport-segment DNA by the central domain of type IIA topoisomerases.Science advances · 2025Article
- Mechanism of Action of Gepotidacin: Well-Balanced Dual-Targeting againstACS infectious diseases · 2025Article
- A network pharmacology-based approach to understand the mechanism of action of anti-mycobacterial activity of Acacia nilotica: a modelling and experimental study.Molecular diversity · 2025Article
- Anti-Mycobacterial Activity of Bacterial Topoisomerase Inhibitors with Dioxygenated Linkers.ACS infectious diseases · 2025Article
- DNA Decatenation Catalyzed by Bacterial Topoisomerase IV.Methods in molecular biology (Clifton, N.J.) · 2025Article
- DNA Supercoiling Catalyzed by Bacterial Gyrase.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Article
- Rifampicin and isoniazid resistance not promote fluoroquinolone resistance in Mycobacterium smegmatis.PloS one · 2025Article
- DNA Cleavage Mediated by Bacterial Type II Topoisomerases.Methods in molecular biology (Clifton, N.J.) · 2025Article
- How Do Gepotidacin and Zoliflodacin Stabilize DNA-Cleavage Complexes with Bacterial Type IIA Topoisomerases? 2. A Single Moving Metal Mechanism.International journal of molecular sciences · 2024Article
- Deep learning-based prediction of chemical accumulation in a pathogenic mycobacterium.bioRxiv : the preprint server for biology · 2024Article
- Interactions between Zoliflodacin andACS infectious diseases · 2024Article
- Interactions between Gepotidacin andACS infectious diseases · 2024Article
- Gyrase and Topoisomerase IV: Recycling Old Targets for New Antibacterials to Combat Fluoroquinolone Resistance.ACS infectious diseases · 2024Review
- Target-Mediated Fluoroquinolone Resistance inACS infectious diseases · 2024Article
1 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 4 institutions in 2 countries.
Funding
Abstract
Mycobacterium tuberculosis is a significant source of global morbidity and mortality. Moxifloxacin and other fluoroquinolones are important therapeutic agents for the treatment of tuberculosis, particularly multidrug-resistant infections. To guide the development of new quinolone-based agents, it is critical to understand the basis of drug action against M. tuberculosis gyrase and how mutations in the enzyme cause resistance. Therefore, we characterized interactions of fluoroquinolones and related drugs with WT gyrase and enzymes carrying mutations at GyrA(A90) and GyrA(D94). M. tuberculosis gyrase lacks a conserved serine that anchors a water-metal ion bridge that is critical for quinolone interactions with other bacterial type II topoisomerases. Despite the fact that the serine is replaced by an alanine (i.e., GyrA(A90)) in M. tuberculosis gyrase, the bridge still forms and plays a functional role in mediating quinolone-gyrase interactions. Clinically relevant mutations at GyrA(A90) and GyrA(D94) cause quinolone resistance by disrupting the bridge-enzyme interaction, thereby decreasing drug affinity. Fluoroquinolone activity against WT and resistant enzymes is enhanced by the introduction of specific groups at the C7 and C8 positions. By dissecting fluoroquinolone-enzyme interactions, we determined that an 8-methyl-moxifloxacin derivative induces high levels of stable cleavage complexes with WT gyrase and two common resistant enzymes, GyrA(A90V) and GyrA(D94G). 8-Methyl-moxifloxacin was more potent than moxifloxacin against WT M. tuberculosis gyrase and displayed higher activity against the mutant enzymes than moxifloxacin did against WT gyrase. This chemical biology approach to defining drug-enzyme interactions has the potential to identify novel drugs with improved activity against tuberculosis.
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