A High-Throughput Screen To Identify Inhibitors of ATP Homeostasis in Non-replicating Mycobacterium tuberculosis
| Autor: | Jun Zheng, Boon Heng Lee, Mai Ping Tan, Arnab K. Chatterjee, Pamela Thayalan, Thomas Dick, Vivian Lim, Richard Glynne, Puiying A. Mak, Seow Hwee Ng, Ngai Ling Ma, Xiuhua Lin, rd Clifton E. Barry, Frantisek Supek, Srinivasa P. S. Rao, Joseph Cherian, Joann Tay, Helena I. Boshoff, Bee Huat Tan, Luis R. Camacho, Jeyaraj Duraiswamy, Kevin Pethe, Pablo Bifani, Kelli Kuhen, David Beer, Jason Chyba |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Tuberculosis
Cell Survival Antitubercular Agents CHO Cells Biochemistry Microbiology Mycobacterium tuberculosis 03 medical and health sciences chemistry.chemical_compound Adenosine Triphosphate Cricetulus Cricetinae medicine Animals Homeostasis Humans Cell survival 030304 developmental biology 0303 health sciences Mycobacterium bovis biology 030306 microbiology Chinese hamster ovary cell General Medicine Articles biology.organism_classification medicine.disease Virology 3. Good health High-Throughput Screening Assays chemistry Molecular Medicine Adenosine triphosphate Intracellular HeLa Cells |
| Zdroj: | ACS Chemical Biology |
| ISSN: | 1554-8937 1554-8929 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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