Work

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

Year: 2024

Type: article

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.

Source: iScience

DOI: 10.1016/j.isci.2024.110967