Fatty acid metabolism of Mycobacterium tuberculosis: a double-edged sword

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) Fatty acid metabolism of Mycobacterium tuberculosis: a double-edged sword. Microbial Cell, 13 (1). (In Press)

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Unlike other heterotrophic bacteria, Mycobacterium tuberculosis (Mtb) can co-catabolize a range of carbon sources simultaneously. Evolution of Mtb within host nutrient environment allows Mtb to consume the host’s fatty acids as a main carbon source during infec- tion. The fatty acid-induced metabolic advantage greatly contributes to Mtb’s pathogenicity and viru- lence. Thus, the identification of key enzymes involved in Mtb’s fatty acid metabolism is urgently needed to aid new drug development. Two fatty acid metabolism enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and isocitrate lyase (ICL) have been intensively studied as promising drug targets, but recently, Quinonez et al. (mBio, doi: 10.1128/mbio.03559-21) highlighted a link between the fatty acid-induced dormancy-like state and drug tolerance. Using metabolomics profiling of a PEPCK-deficient mutant, Quinonez et al. identified that over-accumulation of methylcitrate cycle (MCC) inter- mediates are phenotypically associated with enhanced drug tolerance against first- and second- line TB antibi- otics. This finding was further corroborated by metabolomics and phenotypic characterization of Mtb mutants lacking either ICL or 2-methylcitrate dehydra- tase. Fatty acid metabolism induced drug-tolerance was also recapitulated in wildtype Mtb after treatment with authentic 2-methylisocitrate, an MCC intermedi- ate. Together, the fatty acid-induced dormancy-like state and drug tolerance are attributed to dysregulat- ed MCC activity.

Item Type: Article
Additional Information: © 2022 Quinonez et al. 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, the Company of Biologists, Biochemical Society, and the University of Westminster to S.R.
Uncontrolled Keywords: tuberculosis, metabolomics, drug tolerance, fatty acids, methylcitrate cycle
Subjects: Medicine and health > Microbiology
Medicine and health
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Depositing User: Amarachukwu Anyogu
Date Deposited: 28 Feb 2022 19:04
Last Modified: 04 Mar 2022 15:18
URI: http://repository.uwl.ac.uk/id/eprint/8811


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