High-throughput screen with the l,d-transpeptidase Ldt_Mt2 of <i>Mycobacterium tuberculosis</i> reveals novel classes of covalently reacting inhibitors.

ABSTRACT: Disruption of bacterial cell wall biosynthesis in Mycobacterium tuberculosis is a promising target for treating tuberculosis. The l,d-transpeptidase Ldt_Mt2, which is responsible for the formation of 3 → 3 cross-links in the cell wall peptidoglycan, has been identified as essential for M. tuberculosis virulence. We optimised a high-throughput assay for Ldt_Mt2, and screened a targeted library of ∼10 000 electrophilic compounds. Potent inhibitor classes were identified, including established (e.g., β-lactams) and unexplored covalently reacting electrophilic groups (e.g., cyanamides). Protein-observed mass spectrometric studies reveal most classes to react covalently and irreversibly with the Ldt_Mt2 catalytic cysteine (Cys354). Cryst

SUBMITTER: de Munnik M 

PROVIDER: S-EPMC10321483 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature