1. Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site.
- Author
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Mendes V, Green SR, Evans JC, Hess J, Blaszczyk M, Spry C, Bryant O, Cory-Wright J, Chan DS, Torres PHM, Wang Z, Nahiyaan N, O'Neill S, Damerow S, Post J, Bayliss T, Lynch SL, Coyne AG, Ray PC, Abell C, Rhee KY, Boshoff HIM, Barry CE 3rd, Mizrahi V, Wyatt PG, and Blundell TL
- Subjects
- Allosteric Regulation drug effects, Allosteric Site drug effects, Antitubercular Agents therapeutic use, Bacterial Proteins genetics, Bacterial Proteins metabolism, Bacterial Proteins ultrastructure, Carboxy-Lyases genetics, Carboxy-Lyases metabolism, Carboxy-Lyases ultrastructure, Coenzyme A biosynthesis, Crystallography, X-Ray, Enzyme Assays, Gene Knockdown Techniques, High-Throughput Screening Assays, Humans, Microbial Sensitivity Tests, Mycobacterium tuberculosis enzymology, Mycobacterium tuberculosis genetics, Peptide Synthases genetics, Peptide Synthases metabolism, Peptide Synthases ultrastructure, Tuberculosis drug therapy, Tuberculosis microbiology, Antitubercular Agents pharmacology, Bacterial Proteins antagonists & inhibitors, Carboxy-Lyases antagonists & inhibitors, Mycobacterium smegmatis enzymology, Mycobacterium tuberculosis drug effects, Peptide Synthases antagonists & inhibitors
- Abstract
Coenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, and its biosynthetic pathway has raised substantial interest as a drug target against multiple pathogens including Mycobacterium tuberculosis. The biosynthesis of CoA is performed in five steps, with the second and third steps being catalysed in the vast majority of prokaryotes, including M. tuberculosis, by a single bifunctional protein, CoaBC. Depletion of CoaBC was found to be bactericidal in M. tuberculosis. Here we report the first structure of a full-length CoaBC, from the model organism Mycobacterium smegmatis, describe how it is organised as a dodecamer and regulated by CoA thioesters. A high-throughput biochemical screen focusing on CoaB identified two inhibitors with different chemical scaffolds. Hit expansion led to the discovery of potent and selective inhibitors of M. tuberculosis CoaB, which we show to bind to a cryptic allosteric site within CoaB.
- Published
- 2021
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