Validation of CoaBC as a Bactericidal Target in the Coenzyme A Pathway of Mycobacterium tuberculosis

Mycobacterium tuberculosis relies on its own ability to biosynthesize coenzyme A to meet the needs of the myriad enzymatic reactions that depend on this cofactor for activity. As such, the essential pantothenate and coenzyme A biosynthesis pathways have attracted attention as targets for tuberculosi...

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Bibliographic Details
Published in:ACS infectious diseases 2016-12, Vol.2 (12), p.958-968
Main Authors: Evans, Joanna C, Trujillo, Carolina, Wang, Zhe, Eoh, Hyungjin, Ehrt, Sabine, Schnappinger, Dirk, Boshoff, Helena I. M, Rhee, Kyu Y, Barry, Clifton E, Mizrahi, Valerie
Format: Article
Language:English
Subjects:
Animals
Antitubercular Agents - chemistry
Bacterial Proteins - antagonists & inhibitors
Bacterial Proteins - genetics
Bacterial Proteins - metabolism
Coenzyme A - metabolism
Enzyme Inhibitors - administration & dosage
Enzyme Inhibitors - chemistry
Female
Humans
Mice
Mice, Inbred C57BL
Mycobacterium tuberculosis - drug effects
Mycobacterium tuberculosis - enzymology
Mycobacterium tuberculosis - genetics
Peptide Synthases - antagonists & inhibitors
Peptide Synthases - genetics
Peptide Synthases - metabolism
Tuberculosis - drug therapy
Tuberculosis - microbiology
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Summary:Mycobacterium tuberculosis relies on its own ability to biosynthesize coenzyme A to meet the needs of the myriad enzymatic reactions that depend on this cofactor for activity. As such, the essential pantothenate and coenzyme A biosynthesis pathways have attracted attention as targets for tuberculosis drug development. To identify the optimal step for coenzyme A pathway disruption in M. tuberculosis, we constructed and characterized a panel of conditional knockdown mutants in coenzyme A pathway genes. Here, we report that silencing of coaBC was bactericidal in vitro, whereas silencing of panB, panC, or coaE was bacteriostatic over the same time course. Silencing of coaBC was likewise bactericidal in vivo, whether initiated at infection or during either the acute or chronic stages of infection, confirming that CoaBC is required for M. tuberculosis to grow and persist in mice and arguing against significant CoaBC bypass via transport and assimilation of host-derived pantetheine in this animal model. These results provide convincing genetic validation of CoaBC as a new bactericidal drug target.
ISSN:2373-8227
2373-8227
DOI:10.1021/acsinfecdis.6b00150