4.5 Article

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

期刊

ACS INFECTIOUS DISEASES
卷 7, 期 6, 页码 1666-1679

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.0c00904

关键词

tuberculosis; drug discovery; coenzyme A; CoaBC

资金

  1. Bill and Melinda Gates Foundation [OPP1024021, OPP1158806]
  2. South African Medical Research Council
  3. National Research Foundation of South Africa
  4. HHMI
  5. NIAID
  6. Swiss National Science Foundation (SNSF Early PostDoc Mobility Fellowship) [P2ZHP2_164947]
  7. Marie Curie Research Grants Scheme, EU H2020 Framework Programme (H2020-MSCAIF-2017) [789607]
  8. NHMRC Overseas Biomedical Fellowship [1016357]
  9. Bill and Melinda Gates Foundation HIT-TB [OPP1024021]
  10. Wellcome Trust [200814_Z_16_ Z: RG83114]
  11. MRC-CinC [MC_PC_14099]
  12. MRC [MC_PC_14099] Funding Source: UKRI
  13. Swiss National Science Foundation (SNF) [P2ZHP2_164947] Funding Source: Swiss National Science Foundation (SNF)
  14. Marie Curie Actions (MSCA) [789607] Funding Source: Marie Curie Actions (MSCA)
  15. Bill and Melinda Gates Foundation [OPP1024021, OPP1158806] Funding Source: Bill and Melinda Gates Foundation

向作者/读者索取更多资源

Coenzyme A (CoA) is an essential cofactor in all living cells, and the pathway to CoA biosynthesis is considered a potential source of novel tuberculosis drug targets. This study identified a small molecule inhibitor, compound 1f, that displays on-target activity against Mtb CoaBC, confirming the druggability of this target. Metabolomic profiling following exposure to compound 1f in wild-type Mtb H37Rv produced a signature consistent with perturbations in pantothenate and CoA biosynthesis.
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.

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