A High-Throughput Screen against Pantothenate Synthetase (PanC) Identifies 3-Biphenyl-4-Cyanopyrrole-2-Carboxylic Acids as a New Class of Inhibitor with Activity against Mycobacterium tuberculosis
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| Authors: | Anuradha Kumar Allen Casey Joshua Odingo Edward A Kesicki Garth Abrahams Michal Vieth Thierry Masquelin Valerie Mizrahi Philip A Hipskind David R Sherman Tanya Parish |
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| Institution: | 1. Seattle Biomedical Research Institute, Seattle, Washington, United States of America.; 2. TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington, United States of America.; 3. Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.; 4. Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indianapolis, United States of America.; The Ohio State University, United States of America, |
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| Abstract: | The enzyme pantothenate synthetase, PanC, is an attractive drug target in Mycobacterium tuberculosis. It is essential for the in vitro growth of M. tuberculosis and for survival of the bacteria in the mouse model of infection. PanC is absent from mammals. We developed an enzyme-based assay to identify inhibitors of PanC, optimized it for high-throughput screening, and tested a large and diverse library of compounds for activity. Two compounds belonging to the same chemical class of 3-biphenyl-4- cyanopyrrole-2-carboxylic acids had activity against the purified recombinant protein, and also inhibited growth of live M. tuberculosis in manner consistent with PanC inhibition. Thus we have identified a new class of PanC inhibitors with whole cell activity that can be further developed. |
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