The role of fatty acid metabolism in drug tolerance of mycobacterium tuberculosis

Quinonez, Camila G., Lee, Jae Jin, Lim, Juhyeon, Odell, Mark, Lawson, Christopher P., Anyogu, Amarachukwu ORCID: https://orcid.org/0000-0001-9652-7728, Raheem, Saki and Eoh, Hyungjin (2022) The role of fatty acid metabolism in drug tolerance of mycobacterium tuberculosis. mBio, 13 (1).

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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.

Item Type: Article
Additional Information: This work was supported by start-up funding from the Department of Molecular Microbiology and Immunology (Keck School of Medicine, USC), American Lung Association (Innovation Award), and NIH (AI139386 and AI143870) to H.E., and the Quintin Hogg Foundation
Uncontrolled Keywords: tuberculosis, drug tolerance, metabolomics, methylcitrate cycle, fatty acids, acetate, drug tolerance, tuberculosis
Subjects: Medicine and health > Microbiology
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Depositing User: Amarachukwu Anyogu
Date Deposited: 11 Jan 2022 12:42
Last Modified: 12 Jan 2022 09:33
URI: http://repository.uwl.ac.uk/id/eprint/8571

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