2. Academic Validation
  3. Molecular mechanism of a triazole-containing inhibitor of Mycobacterium tuberculosis DNA gyrase

Molecular mechanism of a triazole-containing inhibitor of Mycobacterium tuberculosis DNA gyrase

  • iScience. 2024 Sep 16;27(10):110967. doi: 10.1016/j.isci.2024.110967.
Antoine Gedeon 1,  Emilie Yab 1,  Aurelia Dinut 2,  Elodie Sadowski 3,  Estelle Capton 3,  Aurore Dreneau 2,  Julienne Petit 1,  Bruna Gioia 2,  Catherine Piveteau 2,  Kamel Djaout 4,  Estelle Lecat 1,  Anne Marie Wehenkel 1 5,  Francesca Gubellini 1,  Ariel Mechaly 6,  Pedro M Alzari 1,  Benoît Deprez 2,  Alain Baulard 4,  Alexandra Aubry 3,  Nicolas Willand 2,  Stéphanie Petrella 1 5
Affiliations

Affiliations

  • 1 Institut Pasteur, Université Paris Cité, CNRS UMR 3528, Unité de Microbiologie Structurale, 75015 Paris, France.
  • 2 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for living Systems, 59000 Lille, France.
  • 3 Cimi-Paris, INSERM U1135, Sorbonne Université, AP-HP. Sorbonne Université, Laboratoire de Bactériologie-Hygiène, CNR des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux, 75005 Paris, France.
  • 4 Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, 59000 Lille, France.
  • 5 Institut Pasteur, Université Paris Cité, CNRS UMR 3528, Bacterial Cell Cycle Mechanisms Unit, 75015 Paris, France.
  • 6 Institut Pasteur, Plate-Forme de Cristallographie, CNRS UMR 3528, 75015 Paris, France.
PMID: 39429773 DOI: 10.1016/j.isci.2024.110967
Abstract

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 Mycobacterium tuberculosis (Mtb). Moreover, one hit, compound 10a, named BDM71403, was shown to be more potent in Mtb than the NBTI of reference, gepotidacin. Mechanistic enzymology assays reveal a competitive interaction of BDM71403 with fluoroquinolones within the Mtb gyrase cleavage core. High-resolution cryo-electron microscopy structural analysis provides detailed insights into the ternary complex formed by the Mtb gyrase, double-stranded DNA, and either BDM71403 or gepotidacin, providing a rational framework to understand the superior in vitro efficacy on Mtb. 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.

Keywords

Drugs; Microbiology; Molecular Structure; Multidrug resistant organisms.

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