Molecular mechanism of a triazole-containing inhibitor of Mycobacterium tuberculosis DNA gyrase
Antimicrobial resistance remains a persistent and pressing public health concern. Here, we describe the synthesis of original triazole-containing inhibitors targeting the DNA gyrase, a well-validated drug target for developing new antibiotics. Our compounds demonstrate potent antibacterial activity against various pathogenic bacteria, with notable potency against <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>). Moreover, one hit, compound <b>10a</b>, named BDM71403, was shown to be more potent in <i>Mtb</i> than the NBTI of reference, gepotidacin. Mechanistic enzymology assays reveal a competitive interaction of BDM71403 with fluoroquinolones within the <i>Mtb</i> gyrase cleavage core. High-resolution cryo-electron microscopy structural analysis provides detailed insights into the ternary complex formed by the <i>Mtb</i> gyrase, double-stranded DNA, and either BDM71403 or gepotidacin, providing a rational framework to understand the superior <i>in vitro</i> efficacy on <i>Mtb</i>. This study highlights the potential of triazole-based scaffolds as promising gyrase inhibitors, offering new avenues for drug development in the fight against antimicrobial resistance.
Authors
- Francesca Gubellini (ORCID: https://orcid.org/0000-0002-2155-9765)
- Pedro M. Alzari (ORCID: https://orcid.org/0000-0002-4233-1903)
- Julienne Petit (ORCID: https://orcid.org/0000-0002-2312-4044)
- Ariel Méchaly (ORCID: https://orcid.org/0000-0002-5305-7495)
- Anne Marie Wehenkel (ORCID: https://orcid.org/0000-0003-2327-6512)
- Antoine Gedeon (ORCID: https://orcid.org/0000-0003-0301-8786)
- Emilie Yab
- Kamel Djaout (ORCID: https://orcid.org/0000-0002-5531-9882)
- Bruna Gioia
- Estelle Capton (ORCID: https://orcid.org/0000-0002-6046-3387)
- Alain R. Baulard (ORCID: https://orcid.org/0000-0002-0150-5241)
- S. Petrella (ORCID: https://orcid.org/0000-0001-6641-5901)
- Catherine Piveteau (ORCID: https://orcid.org/0000-0002-3835-4619)
- Aurore Dreneau (ORCID: https://orcid.org/0000-0002-8794-8173)
- Nicolas Willand (ORCID: https://orcid.org/0000-0002-0784-0462)
- Benoit P. Deprez (ORCID: https://orcid.org/0000-0002-2777-4538)
- Alexandra Aubry (ORCID: https://orcid.org/0000-0003-4230-4793)
- Estelle Lecat
- Aurelia Dinut
- Elodie Sadowski
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Institut Pasteur (FR)
- Université Paris Cité (FR)
- Université de Lille (FR)
- Institut Pasteur de Lille (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- Sorbonne Université (FR)
- Laboratoire de Cristallographie et RMN Biologiques (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Center for Infection and Immunity of Lille (FR)
- Université Paris 1 Panthéon-Sorbonne (FR)
Publication Details
- Journal
- iScience
- Published
- 2024-09-17
- DOI
- https://doi.org/10.1016/j.isci.2024.110967
- Citations
- 4
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 1.56
Funders
- European Molecular Biology Laboratory
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Centre National de la Recherche Scientifique
- Université de Paris