期刊
ACS INFECTIOUS DISEASES
卷 2, 期 12, 页码 70-80出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.6b00150
关键词
tuberculosis; drug discovery; CoA; pantetheine; CoaBC
资金
- TB Drug Accelerator program of the Bill and Melinda Gates Foundation
- South African Medical Research Council
- National Research Foundation of South Africa
- International Research Scholar's grant from the HHMI
- Intramural Research Program of NIAID
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.
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