High-throughput screen identifies small molecule inhibitors targeting acetyltransferase activity of Mycobacterium tuberculosis GlmU

Tuberculosis
Chitra RaniInshad Ali Khan

Abstract

N-acetylglucosamine-1-phosphate uridyltransferase (GlmU) is a pivotal bifunctional enzyme, its N and C terminal domains catalyzes uridyltransferase and acetyltransferase activities, respectively. Final product of GlmU catalyzed reaction, uridine-diphospho-N-acetylglucosamine (UDP-GlcNAc), acts as sugar donor providing GlcNAc residues in the synthesis of peptidoglycan and a disaccharide linker (D-N-GlcNAc-1-rhamnose), the key structural components of Mycobacterium tuberculosis (M. tuberculosis) cell wall. In the present study, we have searched new inhibitors against acetyltransferase activity of M. tuberculosis GlmU. A subset of 1607 synthetic compounds, selected through dual approach i.e., in-silico and whole cell screen against 20,000 compounds from ChemBridge library, was further screened using an in-vitro high throughput bioassay to identify inhibitors of acetyltransferase domain of M. tuberculosis GlmU. Four compounds were found to inhibit GlmU enzyme specific to acetyltransferase activity, with IC50 values ranging from 9 to 70 μM. Two compounds (6624116, 5655606) also exhibited whole cell activity against drug susceptible as well as drug resistant M. tuberculosis. These two compounds also exhibited increased anti-TB activi...Continue Reading

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Citations

Feb 19, 2016·Applied Microbiology and Biotechnology·Vikrant S RajputInshad Ali Khan
Dec 23, 2015·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Chitra Rani, Inshad Ali Khan
Feb 26, 2019·Frontiers in Microbiology·Maria João CatalãoMadalena Pimentel
Sep 21, 2018·Glycoconjugate Journal·Tripti RaghavendraRaju Mukherjee
Aug 7, 2017·Nature Communications·João P PiscoLuiz Pedro S de Carvalho

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