N-Acetylglucosamine-1-phosphate transferase, WecA, as a validated drug target in Mycobacterium tuberculosis [PublishAheadOfPrint]

The mycobacterial phosphoglycosyltransferase, WecA, which initiates arabinogalactan biosynthesis in Mycobacterium tuberculosis, has been proposed as a target of the caprazamycin derivative, CPZEN-45, a preclinical drug candidate for treatment of tuberculosis. In this report, we describe the functional characterization of mycobacterial WecA and confirm the essentiality of its encoding gene in M. tuberculosis by demonstrating that transcriptional silencing of wecA is bactericidal in vitro and in macrophages. Silencing of wecA also conferred hypersensitivity of M. tuberculosis to the drug, tunicamycin, confirming its target selectivity for WecA in whole cells. Simple radiometric assays performed with mycobacterial membranes and commercially available substrates, allowed chemical validation of other putative WecA inhibitors, as well as resolving their selectivity towards WecA versus another attractive cell wall target - translocase I that catalyzes the first membrane step in biosynthesis of peptidoglycan. These assays and mutant strain described herein will be useful for identifying potential antitubercular leads by screening chemical libraries for novel WecA inhibitors.

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