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TitleDiscovery of isoquinoline sulfonamides as allosteric gyrase inhibitors with activity against fluoroquinolone-resistant bacteria.
Journal, issue, pagesNat Chem, Year 2024
Publish dateJun 19, 2024
AuthorsAlexander T Bakker / Ioli Kotsogianni / Mariana Avalos / Jeroen M Punt / Bing Liu / Diana Piermarini / Berend Gagestein / Cornelis J Slingerland / Le Zhang / Joost J Willemse / Leela B Ghimire / Richard J H B N van den Berg / Antonius P A Janssen / Tom H M Ottenhoff / Constant A A van Boeckel / Gilles P van Wezel / Dmitry Ghilarov / Nathaniel I Martin / Mario van der Stelt /
PubMed AbstractBacteria 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 ...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.
External linksNat Chem / PubMed:38898213
MethodsEM (single particle)
Resolution2.9 Å
Structure data

18592

8qqi

EMDB-18592, PDB-8qqi:
E.coli DNA gyrase in complex with 217 bp substrate DNA and LEI-800
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals


ChemComp, No image

ChemComp-LRL:
Unknown entry

ChemComp-MG:
Unknown entry

Source
  • escherichia coli (E. coli)
  • escherichia phage mu (virus)
KeywordsDNA BINDING PROTEIN / TOPOISOMERASE / GYRASE / ALLOSTERIC INHIBITOR / ANTIBIOTIC

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