Targeting Mycobacterium tuberculosis CoaBC through Chemical Inhibition of 4'-Phosphopantothenoyl-l-cysteine Synthetase (CoaB) Activity

Coenzyme A (CoA) is a ubiquitous cofactor present in all living cells and estimated to be required for up to 9% of intracellular enzymatic reactions. Mycobacterium tuberculosis (Mtb) relies on its own ability to biosynthesize CoA to meet the needs of the myriad enzymatic reactions that depend on this cofactor for activity. As such, the pathway to CoA biosynthesis is recognized as a potential source of novel tuberculosis drug targets. In prior work, we genetically validated CoaBC as a bactericidal drug target in Mtb in vitro and in vivo. Here, we describe the identification of compound 1f, a small molecule inhibitor of the 4′-phosphopantothenoyl-l-cysteine synthetase (PPCS; CoaB) domain of the bifunctional Mtb CoaBC, and show that this compound displays on-target activity in Mtb. Compound 1f was found to inhibit CoaBC uncompetitively with respect to 4′-phosphopantothenate, the substrate for the CoaB-catalyzed reaction. Furthermore, metabolomic profiling of wild-type Mtb H37Rv following exposure to compound 1f produced a signature consistent with perturbations in pantothenate and CoA biosynthesis. As the first report of a direct small molecule inhibitor of Mtb CoaBC displaying target-selective whole-cell activity, this study confirms the druggability of CoaBC and chemically validates this target. ; This work was supported by HIT-TB (OPP1024021) and SHORTEN-TB (OPP1158806) grants from the TB Drug Accelerator program of the Bill and Melinda Gates Foundation (to C. E. Barry III, K. Y. Rhee, and V. Mizrahi), the South African Medical Research Council, the National Research Foundation of South Africa, and an International Research Scholar’s grant from the HHMI (to V. Mizrahi) and, in part, by the Intramural Research Program of NIAID (H. I. M. Boshoff and C. E. Barry III). J. Hess was financially supported by the Swiss National Science Foundation (SNSF Early PostDoc Mobility Fellowship, P2ZHP2_164947) and the Marie Curie Research Grants Scheme, EU H2020 Framework Programme (H2020-MSCAIF-2017, ID: 789607). C. Spry was ...