Discovery of isoquinoline sulfonamides as allosteric gyrase inhibitors with activity against fluoroquinolone-resistant bacteria

Journal article

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.Immunogenetics and cellular immunology of bacterial infectious disease

Authors: Bakker, AT; Kotsogianni, I; Avalos, M; Punt, JM; Liu, B

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Chemistry
• Volume: 16
• Issue: 9
• Pages: 1462-1472
• Publication date: 2024-06-19
• DOI: 10.1038/s41557-024-01516-x
• EISSN: 1755-4349
• ISSN: 1755-4330
• Language: English
• Keywords: Mode of action; Genetics; Biochemistry; Enzyme; Antibacterial activity; Chemistry; Stereochemistry; Biology; Isoquinoline; Escherichia coli; Microbiology; Bacteria; Allosteric regulation; Gene; Topoisomerase IV; DNA gyrase