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

Nat Chem. 2024 Jun 19. doi: 10.1038/s41557-024-01516-x.

Alexander T Bakker ^# ¹, Ioli Kotsogianni ^# ², Mariana Avalos ³, Jeroen M Punt ¹, Bing Liu ¹, Diana Piermarini ¹, Berend Gagestein ¹, Cornelis J Slingerland ², Le Zhang ³, Joost J Willemse ³, Leela B Ghimire ⁴, Richard J H B N van den Berg ¹, Antonius P A Janssen ¹, Tom H M Ottenhoff ⁵, Constant A A van Boeckel ¹, Gilles P van Wezel ³, Dmitry Ghilarov ⁶, Nathaniel I Martin ⁷, Mario van der Stelt ⁸

Affiliations

1 Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
2 Biological Chemistry Group, Institute of Biology, Leiden University, Leiden, the Netherlands.
3 Department of Molecular Biotechnology, Institute of Biology, Leiden University, Leiden, the Netherlands.
4 Department of Molecular Microbiology, John Innes Centre, Norwich, UK.
5 Department of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands.
6 Department of Molecular Microbiology, John Innes Centre, Norwich, UK. dmitry.ghilarov@jic.ac.uk.
7 Biological Chemistry Group, Institute of Biology, Leiden University, Leiden, the Netherlands. n.i.martin@biology.leidenuniv.nl.
8 Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands. m.van.der.stelt@chem.leidenuniv.nl.
# Contributed equally.

PMID: 38898213 DOI: 10.1038/s41557-024-01516-x

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-159048

LEI-800

DNA gyrase Inhibitor

DNA/RNA Synthesis; Bacterial

Infection

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