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

The l,d-transpeptidases (Ldts) are promising antibiotic targets for treating tuberculosis. We report screening of cysteine-reactive inhibitors against LdtMt2 from Mycobacterium tuberculosis. Structural studies on LdtMt2 with potent inhibitor ebselen reveal opening of the benzisoselenazolone ring by...

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Bibliographic Details
Published in:Chemical communications (Cambridge, England) England), 2019-08, Vol.55 (69), p.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: Article
Language:English
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
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Summary:The l,d-transpeptidases (Ldts) are promising antibiotic targets for treating tuberculosis. We report screening of cysteine-reactive inhibitors against LdtMt2 from Mycobacterium tuberculosis. Structural studies on LdtMt2 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.
ISSN:1359-7345
1364-548X
DOI:10.1039/C9CC04145A