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Discovery of WecA inhibitors for development of new TB drugs for dormant Mycobacterium tuberculosis infections

International Conference on Glycobiology
September 21-22, 2017 HOUSTON, TX, USA

Michio Kurosu

University of Tennessee, USA

Posters & Accepted Abstracts: Eur J Exp Bio


The emergence of multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (Mtb) seriously threatens TB control and prevention efforts. In general TB chemotherapy, treatment length can be up to two years for infections of MDR strains and can be longer for extensively drug-resistant (XDR) strains. Thus, it is an important program to discover promising approaches to the shortening of current TB drug regimen. Mechanisms that enter non-replicating (or dormant) state of Mtb are accounted for a significant factor that requires long-term chemotherapy and new drugs that target non-replicating Mtb are likely to revolutionize TB chemotherapy. WecA, a phosphotransferase that catalyzes the transformation of prenyl-diphosphoryl-GlcNAc from UDP-GlcNAc and decaprenylphosphate, is essential in growth of Mtb under aerobic conditions and to survive for Mtb in macrophages under oxygen-depleted conditions. Our group developed a convenient assay method against WecA using the modified enzymatic substrates and an assay method to determine bactericidal effect of molecules against intracellular Mtb. As the results of screening of capuramycin-based analogs via our methods, we identified strong WecA inhibitors (low nanomol range concentrations) that kill replicating and non-replicating Mtb. The details of assay development and in vitro assay data for the identified anti-mycobacterial WecA inhibitors will be presented.