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The Role of Fatty Acid Metabolism in Drug Tolerance of Mycobacterium tuberculosis
10.1128/mbio.03559-21
Camila G. Quinonez
Jae Jin Lee
Juhyeon Lim
Mark Odell
Christopher P. Lawson
Amararachukwu Anyogu
Saki Raheem
Hyungjin Eoh
Research Article
Research Article
tuberculosis
drug tolerance
metabolomics
methylcitrate cycle
fatty acids
acetate
drug tolerance
tuberculosis
American Society for Microbiology
Quinonez et al.
Copyright © 2022 Quinonez et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
20220111
2022
ABSTRACT
Mycobacterium tuberculosis can cocatabolize a range of carbon sources. Fatty acids are among the carbons available inside the host’s macrophages. Here, we investigated the metabolic changes of the fatty acid-induced dormancy-like state of M. tuberculosis and its involvement in the acquisition of drug tolerance. We conducted metabolomics profiling using a phosphoenolpyruvate carboxykinase (PEPCK)-deficient M. tuberculosis strain in an acetate-induced dormancy-like state, highlighting an overaccumulation of methylcitrate cycle (MCC) intermediates that correlates with enhanced drug tolerance against isoniazid and bedaquiline. Further metabolomics analyses of two M. tuberculosis mutants, an ICL knockdown (KD) strain and PrpD knockout (KO) strain, each lacking an MCC enzyme—isocitrate lyase (ICL) and 2-methylcitrate dehydratase (PrpD), respectively—were conducted after treatment with antibiotics. The ICL KD strain, which lacks the last enzyme of the MCC, showed an overaccumulation of MCC intermediates and a high level of drug tolerance. The PrpD KO strain, however, failed to accumulate MCC intermediates as it lacks the second step of the MCC and showed only a minor level of drug tolerance compared to the ICL KD mutant and its parental strain (CDC1551). Notably, addition of authentic 2-methylisocitrate, an MCC intermediate, improved the M. tuberculosis drug tolerance against antibiotics even in glycerol medium. Furthermore, wild-type M. tuberculosis displayed levels of drug tolerance when cultured in acetate medium significantly greater than those in glycerol medium. Taken together, the fatty acid-induced dormancy-like state remodels the central carbon metabolism of M. tuberculosis that is functionally relevant to acquisition of M. tuberculosis drug tolerance.
IMPORTANCE Understanding the mechanisms underlying M. tuberculosis adaptive strategies to achieve drug tolerance is crucial for the identification of new targets and the development of new drugs. Here, we show that acetate medium triggers a drug-tolerant state in M. tuberculosis when challenged with antituberculosis (anti-TB) drugs. This carbon-induced drug-tolerant state is linked to an accumulation of the methylcitrate cycle (MCC) intermediates, whose role was previously known as a detox pathway for propionate metabolism. Three mutant strains with mutations in gluconeogenesis and MCC were used to investigate the correlation between drug tolerance and the accumulation of MCC metabolites. We herein report a new role of the MCC used to provide a survival advantage to M. tuberculosis as a species against both anti-TB drugs upon specific carbon sources.
20211124
20211202
2150-7511
Adobe LiveCycle PDF Generator; modified using iText® 5.5.13.2 ©2000-2020 iText Group NV (AGPL-version)2022-01-11T04:10:18-08:00
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