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Discovery of isoquinoline sulfonamides as allosteric gyrase inhibitors with activity against fluoroquinolone-resistant bacteria.
- Source :
-
Nature chemistry [Nat Chem] 2024 Sep; Vol. 16 (9), pp. 1462-1472. Date of Electronic Publication: 2024 Jun 19. - Publication Year :
- 2024
-
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.<br /> (© 2024. The Author(s).)
- Subjects :
- Microbial Sensitivity Tests
Structure-Activity Relationship
Drug Discovery
Allosteric Regulation drug effects
Topoisomerase II Inhibitors pharmacology
Topoisomerase II Inhibitors chemistry
Topoisomerase II Inhibitors chemical synthesis
Isoquinolines chemistry
Isoquinolines pharmacology
Isoquinolines chemical synthesis
Sulfonamides pharmacology
Sulfonamides chemistry
Sulfonamides chemical synthesis
Fluoroquinolones pharmacology
Fluoroquinolones chemistry
Fluoroquinolones chemical synthesis
DNA Gyrase metabolism
Anti-Bacterial Agents pharmacology
Anti-Bacterial Agents chemistry
Anti-Bacterial Agents chemical synthesis
Drug Resistance, Bacterial drug effects
Escherichia coli drug effects
Escherichia coli enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1755-4349
- Volume :
- 16
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Nature chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38898213
- Full Text :
- https://doi.org/10.1038/s41557-024-01516-x