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Abstract
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.
Highlights
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
This compound library predominantly comprises commercially available molecules representing a wide range of chemical space that possessing the favorable physicochemical and molecular properties required for a potential preclinical drug candidate, with a small subset of the library (
Mycobacterium tuberculosis (Mtb) by target-based approaches have largely stalled at the level of whole-cell activity
Summary
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. Tuberculosis (TB) remains the leading cause of death from an infectious disease worldwide, claiming an estimated 1.4 million lives in 2019.1 The high disease burden coupled with the ongoing emergence and spread of strains of Mycobacterium tuberculosis (Mtb) resistant to first- and second-line TB drugs underscores the urgent need to develop new antitubercular agents for the treatment of both drug-resistant and drugsusceptible forms of the disease.[2,3] In recent years, considerable progress has been made in developing a TB drug pipeline,[4] which has begun to deliver promising new drugs and drug combinations.[3,5−8] as attrition rates are high across the entire TB drug pipeline there is an urgent need for replenishment of the pipeline, starting from the earliest stage of hit identification This need is driving drug discovery efforts, which are aimed at delivering high-quality hit compounds with novel mechanisms of action.[9−14]. Potent direct inhibitors of Mtb pantothenate synthetase (PanC, Rv3602c) and pantothenate kinase (PanK, CoaA, Rv1092c) have been developed using this approach, these have failed to translate into lead compounds with significant whole-cell activity against Mtb.[29−32]
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