N -Acetylglucosamine-1-Phosphate Transferase, WecA, as a Validated Drug Target in Mycobacterium tuberculosis

The mycobacterial phosphoglycosyltransferase WecA, which initiates arabinogalactan biosynthesis in , has been proposed as a target of the caprazamycin derivative CPZEN-45, a preclinical drug candidate for the treatment of tuberculosis. In this report, we describe the functional characterization of m...

Full description

Saved in:
Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2017-11, Vol.61 (11)
Main Authors: Huszár, Stanislav, Singh, Vinayak, Polčicová, Alica, Baráth, Peter, Barrio, María Belén, Lagrange, Sophie, Leblanc, Véronique, Nacy, Carol A, Mizrahi, Valerie, Mikušová, Katarína
Format: Article
Language:English
Subjects:
Antitubercular Agents
Biosynthesis
Chemistry
Chemistry
Biosynthesis
Mycobacterium tuberculosis
Transferases (Other Substituted Phosphate Groups)
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The mycobacterial phosphoglycosyltransferase WecA, which initiates arabinogalactan biosynthesis in , has been proposed as a target of the caprazamycin derivative CPZEN-45, a preclinical drug candidate for the treatment of tuberculosis. In this report, we describe the functional characterization of mycobacterial WecA and confirm the essentiality of its encoding gene in by demonstrating that the transcriptional silencing of is bactericidal and in macrophages. Silencing also conferred hypersensitivity of 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 and resolved their selectivity toward WecA versus another attractive cell wall target, translocase I, which catalyzes the first membrane step in the biosynthesis of peptidoglycan. These assays and the mutant strain described herein will be useful for identifying potential antitubercular leads by screening chemical libraries for novel WecA inhibitors.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.01310-17