Journal
NATURE COMMUNICATIONS
Volume 5, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms5306
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Funding
- Bill and Melinda Gates Foundation TB Drug Accelerator program [OPP1024050]
- Burroughs Wellcome Fund Career Award in the Biomedical Sciences
- New York Community Trust Heiser Foundation Fellowship
- William Randolph Hearst Foundation
- Bill and Melinda Gates Foundation [OPP1024050] Funding Source: Bill and Melinda Gates Foundation
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Mycobacterium tuberculosis (Mtb) is a persistent intracellular pathogen intrinsically tolerant to most antibiotics. However, the specific factors that mediate this tolerance remain incompletely defined. Here we apply metabolomic profiling to discover a common set of metabolic changes associated with the activities of three clinically used tuberculosis drugs, isoniazid, rifampicin and streptomycin. Despite targeting diverse cellular processes, all three drugs trigger activation of Mtb's isocitrate lyases (ICLs), metabolic enzymes commonly assumed to be involved in replenishing of tricarboxylic acid (TCA) cycle intermediates. We further show that ICL-deficient Mtb strains are significantly more susceptible than wild-type Mtb to all three antibiotics, and that this susceptibility can be chemically rescued when Mtb is co-incubated with an antioxidant. These results identify a previously undescribed role for Mtb's ICLs in antioxidant defense as a mechanism of antibiotic tolerance.
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