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

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• 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

<i>Mycobacterium tuberculosisi> 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 <i>M. tuberculosisi>, we constructed and characterized a panel of conditional knockdown mutants in coenzyme A pathway genes. Here, we report that silencing of <i>coaBCi> was bactericidal in vitro, whereas silencing of <i>panBi>, <i>panCi>, or <i>coaEi> was bacteriostatic over the same time course. Silencing of <i>coaBCi> 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 <i>M. tuberculosisi> 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.