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

详细信息    查看全文

• 作者：Joanna C. Evans ; Carolina Trujillo ; Zhe Wang ; Hyungjin Eoh ; Sabine Ehrt ; Dirk Schnappinger ; Helena I. M. Boshoff ; Kyu Y. Rhee ; Clifton E. Barry III ; Valerie Mizrahi
• 刊名：ACS Infectious Diseases
• 出版年：2016
• 出版时间：December 9, 2016
• 年：2016
• 卷：2
• 期：12
• 页码：958-968
• 全文大小：646K
• ISSN：2373-8227

文摘

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.