Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site

• DOI: 10.1038/s41467-020-20224-x
• Publication Date: 2021-01-08T11:13:01Z
• Authors: Vitor Mendes; Simon R. Green; Joanna C. Evans; Jeannine Hess; Michal Blaszczyk; Christina Spry; Owain Bryant; James Cory-Wright; Daniel S-H. Chan; Pedro H. M. 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 I. M. Boshoff; Clifton E. Barry; Valerie Mizrahi; Paul G. Wyatt; Tom L. Blundell
• Keywords: Mycobacterium smegmatis; Phosphofructokinase 2

Abstract Coenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, its biosynthetic pathway has raised substantial interest as drug target against multiple pathogens including Mycobacterium tuberculosis . The biosynthesis of CoA performed five steps, with the second third steps being catalysed vast majority prokaryotes, M. , by single bifunctional protein, CoaBC. Depletion CoaBC was found to be bactericidal Here we report first structure full-length CoaBC, from model organism smegmatis describe how it organised dodecamer regulated thioesters. high-throughput biochemical screen focusing on CoaB identified two inhibitors different chemical scaffolds. Hit expansion led discovery potent selective CoaB, which show bind cryptic allosteric site within CoaB.