Targeting the Mycobacterium tuberculosis transpeptidase Ldt Mt2 with cysteine-reactive inhibitors including ebselen

• Published in: Chemical communications (Cambridge, England) Vol. 55; no. 69; pp. 10214 - 10217
• Main Authors: de Munnik, Mariska, Lohans, Christopher T., Lang, Pauline A., Langley, Gareth W., Malla, Tika R., Tumber, Anthony, Schofield, Christopher J., Brem, Jürgen
• Format: Journal Article
• Language: English
• Published: England 22.08.2019
• Subjects: Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Azoles - chemistry; Azoles - pharmacology; Benzene Derivatives - chemistry; Benzene Derivatives - pharmacology; Cysteine - metabolism; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Isoindoles; Molecular Docking Simulation; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - enzymology; Organoselenium Compounds - chemistry; Organoselenium Compounds - pharmacology; Peptidyl Transferases - antagonists & inhibitors; Peptidyl Transferases - metabolism; Tuberculosis - drug therapy; Tuberculosis - microbiology
• ISSN: 1359-7345; 1364-548X
• DOI: 10.1039/C9CC04145A

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.