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

Autor:	Gedeon A; Institut Pasteur, Université Paris Cité, CNRS UMR 3528, Unité de Microbiologie Structurale, 75015 Paris, France., Yab E; Institut Pasteur, Université Paris Cité, CNRS UMR 3528, Unité de Microbiologie Structurale, 75015 Paris, France., Dinut A; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for living Systems, 59000 Lille, France., Sadowski E; 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., Capton E; 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., Dreneau A; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for living Systems, 59000 Lille, France., Petit J; Institut Pasteur, Université Paris Cité, CNRS UMR 3528, Unité de Microbiologie Structurale, 75015 Paris, France., Gioia B; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for living Systems, 59000 Lille, France., Piveteau C; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for living Systems, 59000 Lille, France., Djaout K; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, 59000 Lille, France., Lecat E; Institut Pasteur, Université Paris Cité, CNRS UMR 3528, Unité de Microbiologie Structurale, 75015 Paris, France., Wehenkel AM; Institut Pasteur, Université Paris Cité, CNRS UMR 3528, Unité de Microbiologie Structurale, 75015 Paris, France.; Institut Pasteur, Université Paris Cité, CNRS UMR 3528, Bacterial Cell Cycle Mechanisms Unit, 75015 Paris, France., Gubellini F; Institut Pasteur, Université Paris Cité, CNRS UMR 3528, Unité de Microbiologie Structurale, 75015 Paris, France., Mechaly A; Institut Pasteur, Plate-Forme de Cristallographie, CNRS UMR 3528, 75015 Paris, France., Alzari PM; Institut Pasteur, Université Paris Cité, CNRS UMR 3528, Unité de Microbiologie Structurale, 75015 Paris, France., Deprez B; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for living Systems, 59000 Lille, France., Baulard A; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, 59000 Lille, France., Aubry A; 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., Willand N; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for living Systems, 59000 Lille, France., Petrella S; Institut Pasteur, Université Paris Cité, CNRS UMR 3528, Unité de Microbiologie Structurale, 75015 Paris, France.; Institut Pasteur, Université Paris Cité, CNRS UMR 3528, Bacterial Cell Cycle Mechanisms Unit, 75015 Paris, France.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2024 Sep 16; Vol. 27 (10), pp. 110967. Date of Electronic Publication: 2024 Sep 16 (Print Publication: 2024).
DOI:	10.1016/j.isci.2024.110967
Abstrakt:	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. Competing Interests: The authors declare no competing financial interests. (© 2024 The Author(s).)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu