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

Authors:

Camila G. Quinonez1,2, Jae Jin Lee1, Juhyeon Lim1, Mark Odell3, Christopher P. Lawson4, Amarachukwu Anyogu5, Saki Raheem2 and Hyungjin Eoh1

doi: 10.15698/mic2022.05.777
Volume 9, pp. 123 to 125, published 28/02/2022.

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Affiliations:

1 Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

2 Department of Life Sciences, Faculty of Science and Technology, University of Westminster, London, W1W 6UV, United Kingdom.

3 School of Life Sciences, University of Lincoln, United Kingdom.

4 Stratclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom.

5 School of Biomedical Sciences, University of West London, London, United Kingdom.

Keywords: 

tuberculosis, metabolomics, drug tolerance, fatty acids, methylcitrate cycle

Corresponding Author(s):

Saki Raheem, Department of Life Sciences, Faculty of Science and Technology, University of Westminster, London, W1W 6UV, United Kingdom; s.raheem@westminter.ac.uk Hyungjin Eoh, Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA; heoh@usc.edu

Conflict of interest statement:

The authors declare no conflicts of interest.

Please cite this article as:

Camila G. Quinonez, Jae Jin Lee, Juhyeon Lim, Mark Odell, Christopher P. Lawson, Amarachukwu Anyogu, Saki Raheem and Hyungjin Eoh (2022). Fatty acid metabolism of Mycobacterium tuberculosis: A double-edged sword. Microbial Cell 9(5): 123-125. doi: 10.15698/mic2022.05.777

© 2022 Quinonez et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduc-tion in any medium, provided the original author and source are acknowledged.

Abstract:

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 infection. The fatty acid-induced metabolic advantage greatly contributes to Mtb’s pathogenicity and virulence. 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) intermediates are phenotypically associated with enhanced drug tolerance against first- and second- line TB antibiotics. This finding was further corroborated by metabolomics and phenotypic characterization of Mtb mutants lacking either ICL or 2-methylcitrate dehydratase. Fatty acid metabolism induced drug-tolerance was also recapitulated in wildtype Mtb after treatment with authentic 2-methylisocitrate, an MCC intermediate. Together, the fatty acid-induced dormancy-like state and drug tolerance are attributed to dysregulated MCC activity.