Targeting the Mycobacterium tuberculosis transpeptidase Ldt _Mt2 with cysteine-reactive inhibitors including ebselen†

Abstract

Inhibitors targeting the conserved nucleophilic cysteine of the mycobacterial l, d-transpeptidases are a potential strategy for the treatment of tuberculosis.

Abstract

The l,d-transpeptidases (Ldts) are promising antibiotic targets for treating tuberculosis. We report screening of cysteine-reactive inhibitors against Ldt _Mt2 from Mycobacterium tuberculosis. Structural studies on Ldt _Mt2 with potent inhibitor ebselen reveal opening of the benzisoselenazolone ring by a nucleophilic cysteine, forming a complex involving extensive hydrophobic interactions with a substrate-binding loop.

Notes

†Electronic supplementary information (ESI) available: Experimental details, IC ₅₀ curves, mass spectra, electron density maps. See DOI: 10.1039/c9cc04145a