A high-throughput screen to identify inhibitors of ATP homeostasis in non-replicating Mycobacterium tuberculosis |
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Authors: | Mak Puiying A Rao Srinivasa P S Ping Tan Mai Lin Xiuhua Chyba Jason Tay Joann Ng Seow Hwee Tan Bee Huat Cherian Joseph Duraiswamy Jeyaraj Bifani Pablo Lim Vivian Lee Boon Heng Ling Ma Ngai Beer David Thayalan Pamela Kuhen Kelli Chatterjee Arnab Supek Frantisek Glynne Richard Zheng Jun Boshoff Helena I Barry Clifton E Dick Thomas Pethe Kevin Camacho Luis R |
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Institution: | Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, United States. |
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Abstract: | Growing evidence suggests that the presence of a subpopulation of hypoxic non-replicating, phenotypically drug-tolerant mycobacteria is responsible for the prolonged duration of tuberculosis treatment. The discovery of new antitubercular agents active against this subpopulation may help in developing new strategies to shorten the time of tuberculosis therapy. Recently, the maintenance of a low level of bacterial respiration was shown to be a point of metabolic vulnerability in Mycobacterium tuberculosis. Here, we describe the development of a hypoxic model to identify compounds targeting mycobacterial respiratory functions and ATP homeostasis in whole mycobacteria. The model was adapted to 1,536-well plate format and successfully used to screen over 600,000 compounds. Approximately 800 compounds were confirmed to reduce intracellular ATP levels in a dose-dependent manner in Mycobacterium bovis BCG. One hundred and forty non-cytotoxic compounds with activity against hypoxic non-replicating M. tuberculosis were further validated. The resulting collection of compounds that disrupt ATP homeostasis in M. tuberculosis represents a valuable resource to decipher the biology of persistent mycobacteria. |
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