Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site

Authors list

Vitor Mendes Simon R Green Joanna Evans Jeannine Hess Michal Blaszczyk Christina Spry Owain Bryant James Cory-Wright Daniel S-H Chan Pedro HM Torres Zhe Wang Navid Nahiyaan Sandra O'Neill Sebastian Damerow John Post Tracy Bayliss Sasha L Lynch Anthony G Coyne Peter C Ray Chris Abell Kyu Y Rhee Helena IM Boshoff Clifton E Barry Valerie Mizrahi Paul G Wyatt Tom L Blundell
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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.

Journal details

Journal Nature Communications
Volume 12
Issue number 1
Pages 143
Available online
Publication date

Full text links

Publisher website (DOI) 10.1038/s41467-020-20224-x
Europe PubMed Central 33420031
Pubmed 33420031

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