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

Joanna C. Evans (Lead / Corresponding author), Dinakaran Murugesan, John M. Post, Vitor Mendes, Zhe Wang, Navid Nahiyaan, Sasha L. Lynch, Stephen Thompson, Simon R. Green, Peter C. Ray, Jeannine Hess, Christina Spry, Anthony G. Coyne, Chris Abell, Helena I. M. Boshoff, Paul G. Wyatt, Kyu Y. Rhee, Tom L. Blundell, Clifton E. Barry , Valerie Mizrahi (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)1666-1679
Number of pages14
JournalACS Infectious Diseases
Issue number6
Early online date3 May 2021
Publication statusPublished - 11 Jun 2021


  • tuberculosis
  • drug discovery
  • coenzyme A
  • CoaBC

ASJC Scopus subject areas

  • Infectious Diseases


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