Validation of CoaBC As a Bactericidal Target in the Coenzyme A Pathway of Mycobacterium Tuberculosis

Overview

Journal ACS Infect Dis

Specialties Infectious Diseases
Microbiology
Pharmacology

Date 2016 Sep 28

PMID 27676316

Citations 42

Authors

Joanna C Evans

Carolina Trujillo

Zhe Wang

Hyungjin Eoh

Sabine Ehrt

Dirk Schnappinger

Helena I M Boshoff

Kyu Y Rhee

Clifton E Barry 3rd

Valerie Mizrahi

Affiliations

Soon will be listed here.

Abstract

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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