8S7K

M. tuberculosis gyrase holocomplex with 150 bp DNA and gepotidacin

Summary for 8S7K

• Entry DOI: 10.2210/pdb8s7k/pdb
• EMDB information: 19777
• Descriptor: DNA gyrase subunit A, DNA gyrase subunit B, DNA (5'-D(*AP*GP*TP*AP*TP*TP*AP*CP*CP*CP*CP*TP*TP*CP*CP*GP*GP*A)-3'), ... (6 entities in total)
• Functional Keywords: mycobacterium tuberculosis, dna gyrase, novel bacterial topoisomerase ii inhibitors, antibiotic resistance, structure-activity relation, dna binding protein
• Biological source: Mycobacterium tuberculosis; More
• Total number of polymer chains: 6
• Total formula weight: 426570.24

Authors

Mechaly, A.,Gubellini, F.,Yab, E.,Willand, N.,Petrella, S. (deposition date: 2024-03-01, release date: 2025-10-08, Last modification date: 2026-05-13)

Primary citation

Gedeon, A.,Yab, E.,Dinut, A.,Sadowski, E.,Capton, E.,Dreneau, A.,Petit, J.,Gioia, B.,Piveteau, C.,Djaout, K.,Lecat, E.,Wehenkel, A.M.,Gubellini, F.,Mechaly, A.,Alzari, P.M.,Deprez, B.,Baulard, A.,Aubry, A.,Willand, N.,Petrella, S.
Molecular mechanism of a triazole-containing inhibitor of Mycobacterium tuberculosis DNA gyrase.
Iscience, 27:110967-110967, 2024

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

PubMed: 39429773
DOI: 10.1016/j.isci.2024.110967

Experimental method

ELECTRON MICROSCOPY (3.2 Å)