ArticleNature chemistry2024
Discovery of isoquinoline sulfonamides as allosteric gyrase inhibitors with activity against fluoroquinolone-resistant bacteria.
Article in Nature chemistry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Deciphering competing reaction pathways in the α-C-H functionalization of unprotected alicyclic aminesOrganic chemistry frontiers : an international journal of organic chemistry · 2026Article
- An alkyl-swap platform for late-stage modification of secondary N-methylamines.Nature chemistry · 2026Article
- Characterization of beddomeilactone amide as bacterial DNA gyrase inhibitor: in vitro evaluation and computational insights.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Article
- Study on the structural characteristics of nitrogen-containing compounds in co-pyrolysis tar of low rank coal usingScientific reports · 2026Article
- Direct trapping of the transport-segment DNA by the central domain of type IIA topoisomerases.Science advances · 2025Article
- Recent Advances in Synthetic Isoquinoline-Based Derivatives in Drug Design.Molecules (Basel, Switzerland) · 2025Review
- ENOblock synergizes with colistin to treat Acinetobacter baumannii infections.EMBO molecular medicine · 2025Article
- An Rcs Stress-Based High-Throughput Screen Reveals Novel Gyrase Inhibitors as Indirect Inducers of Cell Envelope Stress in Gram-Negative Bacteria.ACS infectious diseases · 2025Article
- Fighting Antimicrobial Resistance: Innovative Drugs in Antibacterial Research.Angewandte Chemie (International ed. in English) · 2025Review
- Structural basis of chiral wrap and T-segment capture byProceedings of the National Academy of Sciences of the United States of America · 2024Article
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19 authors.
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Abstract
Bacteria have evolved resistance to nearly all known antibacterials, emphasizing the need to identify antibiotics that operate via novel mechanisms. Here we report a class of allosteric inhibitors of DNA gyrase with antibacterial activity against fluoroquinolone-resistant clinical isolates of Escherichia coli. Screening of a small-molecule library revealed an initial isoquinoline sulfonamide hit, which was optimized via medicinal chemistry efforts to afford the more potent antibacterial LEI-800. Target identification studies, including whole-genome sequencing of in vitro selected mutants with resistance to isoquinoline sulfonamides, unanimously pointed to the DNA gyrase complex, an essential bacterial topoisomerase and an established antibacterial target. Using single-particle cryogenic electron microscopy, we determined the structure of the gyrase-LEI-800-DNA complex. The compound occupies an allosteric, hydrophobic pocket in the GyrA subunit and has a mode of action that is distinct from the clinically used fluoroquinolones or any other gyrase inhibitor reported to date. LEI-800 provides a chemotype suitable for development to counter the increasingly widespread bacterial resistance to fluoroquinolones.
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