ArticleProceedings of the National Academy of Sciences of the United States of America2017
Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 84 citations in OpenAlex.
- Click-based determination of accumulation of molecules in Escherichia coli.Nature communications · 2026Article
- Structural interactions of BWC0977 with Klebsiella pneumoniae topoisomerase IV and biochemical basis of its broad-spectrum activity.Communications biology · 2025Article
- Structural Mechanisms of Topoisomerase-Targeting Drugs.Annual review of biochemistry · 2025Review
- Coumarin hybrids: dual-target candidates for future antimicrobial and antitubercular therapies.Future medicinal chemistry · 2025Article
- Total Synthesis and Structural Reassignment of the Antitubercular Natural Product Evybactin.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
- Structural basis of chiral wrap and T-segment capture byProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Machine learning-enabled virtual screening indicates the anti-tuberculosis activity of aldoxorubicin and quarfloxin with verification by molecular docking, molecular dynamics simulations, and biological evaluations.Briefings in bioinformatics · 2024Article
- How Do Gepotidacin and Zoliflodacin Stabilize DNA Cleavage Complexes with Bacterial Type IIA Topoisomerases? 1. Experimental Definition of Metal Binding Sites.International journal of molecular sciences · 2024Article
- Molecular mechanism of a triazole-containing inhibitor ofiScience · 2024Article
- Discovery of isoquinoline sulfonamides as allosteric gyrase inhibitors with activity against fluoroquinolone-resistant bacteria.Nature chemistry · 2024Article
- Interactions between Zoliflodacin andACS infectious diseases · 2024Article
- Article
- Gyrase and Topoisomerase IV: Recycling Old Targets for New Antibacterials to Combat Fluoroquinolone Resistance.ACS infectious diseases · 2024Review
- Thiophene-based lipids for mRNA delivery to pulmonary and retinal tissues.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Friend or Foe: Protein Inhibitors of DNA Gyrase.Biology · 2024Review
- Discovery of PLD4 modulators by high-throughput screening and kinetic analysis.Results in chemistry · 2024Article
- Structure-directed identification of pyridine-2-methylamine derivatives as MmpL3 inhibitors for use as antitubercular agents.European journal of medicinal chemistry · 2023Article
- Developments in Non-Intercalating Bacterial Topoisomerase Inhibitors: Allosteric and ATPase Inhibitors of DNA Gyrase and Topoisomerase IV.Pharmaceuticals (Basel, Switzerland) · 2023Review
- A 2.8 Å Structure of Zoliflodacin in a DNA Cleavage Complex withInternational journal of molecular sciences · 2023Article
- Evybactin is a DNA gyrase inhibitor that selectively kills Mycobacterium tuberculosis.Nature chemical biology · 2022Article
Corrections and comments
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Authors and funding
16 authors at 5 institutions in 4 countries.
Funding
Abstract
A paucity of novel acting antibacterials is in development to treat the rising threat of antimicrobial resistance, particularly in Gram-negative hospital pathogens, which has led to renewed efforts in antibiotic drug discovery. Fluoroquinolones are broad-spectrum antibacterials that target DNA gyrase by stabilizing DNA-cleavage complexes, but their clinical utility has been compromised by resistance. We have identified a class of antibacterial thiophenes that target DNA gyrase with a unique mechanism of action and have activity against a range of bacterial pathogens, including strains resistant to fluoroquinolones. Although fluoroquinolones stabilize double-stranded DNA breaks, the antibacterial thiophenes stabilize gyrase-mediated DNA-cleavage complexes in either one DNA strand or both DNA strands. X-ray crystallography of DNA gyrase-DNA complexes shows the compounds binding to a protein pocket between the winged helix domain and topoisomerase-primase domain, remote from the DNA. Mutations of conserved residues around this pocket affect activity of the thiophene inhibitors, consistent with allosteric inhibition of DNA gyrase. This druggable pocket provides potentially complementary opportunities for targeting bacterial topoisomerases for antibiotic development.
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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.