ArticleAntimicrobial agents and chemotherapy2015
Insights into the mechanism of inhibition of novel bacterial topoisomerase inhibitors from characterization of resistant mutants of Staphylococcus aureus.
Article in Antimicrobial agents and chemotherapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 35 citations in OpenAlex.
- Designing Antibiotics with Inherent Resistance to Efflux as a Strategy to Revive Discovery against Multidrug-Resistant Pathogens.Journal of medicinal chemistry · 2026Article
- Addressing urgent priorities in antibiotic development: insights from WHO 2023 antibacterial clinical pipeline analyses.The Lancet. Microbe · 2025Review
- Gyrase and Topoisomerase IV: Recycling Old Targets for New Antibacterials to Combat Fluoroquinolone Resistance.ACS infectious diseases · 2024Review
- Interactions between Gepotidacin andACS infectious diseases · 2024Article
- Novel bacterial topoisomerase inhibitors: unique targeting activities of amide enzyme-binding motifs for tricyclic analogs.Antimicrobial agents and chemotherapy · 2023Article
- A CcdB toxin-derived peptide acts as a broad-spectrum antibacterial therapeutic in infected mice.EMBO reports · 2023Article
- 1,3-Dioxane-Linked Novel Bacterial Topoisomerase Inhibitors: Expanding Structural Diversity and the Antibacterial Spectrum.ACS medicinal chemistry letters · 2022Article
- Article
- Antibacterial Activity of the Novel Drug Gepotidacin againstAntibiotics (Basel, Switzerland) · 2022Article
- Evaluation of A-azepano-triterpenoids and related derivatives as antimicrobial and antiviral agents.The Journal of antibiotics · 2021Article
- Dioxane-Linked Amide Derivatives as Novel Bacterial Topoisomerase Inhibitors against Gram-PositiveACS medicinal chemistry letters · 2020Article
- Article
- Discovery of a Novel DNA Gyrase-Targeting Antibiotic through the Chemical Perturbation of Streptomyces venezuelae Sporulation.Cell chemical biology · 2019Article
- Novel Bacterial Topoisomerase Inhibitors Exploit Asp83 and the Intrinsic Flexibility of the DNA Gyrase Binding Site.International journal of molecular sciences · 2018Article
- Gepotidacin (GSK2140944)Antimicrobial agents and chemotherapy · 2017Article
- Article
- Suppression of gyrase-mediated resistance by C7 aryl fluoroquinolones.Nucleic acids research · 2016Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The type II topoisomerases DNA gyrase and topoisomerase IV are clinically validated bacterial targets that catalyze the modulation of DNA topology that is vital to DNA replication, repair, and decatenation. Increasing resistance to fluoroquinolones, which trap the topoisomerase-DNA complex, has led to significant efforts in the discovery of novel inhibitors of these targets. AZ6142 is a member of the class of novel bacterial topoisomerase inhibitors (NBTIs) that utilizes a distinct mechanism to trap the protein-DNA complex. AZ6142 has very potent activity against Gram-positive organisms, including Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes. In this study, we determined the frequencies of resistance to AZ6142 and other representative NBTI compounds in S. aureus and S. pneumoniae. The frequencies of selection of resistant mutants at 4× the MIC were 1.7 × 10(-8) for S. aureus and <5.5 × 10(-10) for S. pneumoniae. To improve our understanding of the NBTI mechanism of inhibition, the resistant S. aureus mutants were characterized and 20 unique substitutions in the topoisomerase subunits were identified. Many of these substitutions were located outside the NBTI binding pocket and impact the susceptibility of AZ6142, resulting in a 4- to 32-fold elevation in the MIC over the wild-type parent strain. Data on cross-resistance with other NBTIs and fluoroquinolones enabled the differentiation of scaffold-specific changes from compound-specific variations. Our results suggest that AZ6142 inhibits both type II topoisomerases in S. aureus but that DNA gyrase is the primary target. Further, the genotype of the resistant mutants suggests that domain conformations and DNA interactions may uniquely impact NBTIs compared to fluoroquinolones.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.