期刊
MICROBIAL CELL
卷 9, 期 5, 页码 123-125出版社
SHARED SCIENCE PUBLISHERS OG
DOI: 10.15698/mic2022.05.777
关键词
tuberculosis; metabolomics; drug tolerance; fatty acids; methylcitrate cycle
资金
- Department of Molecular Microbiology and Immunology (Keck School of Medicine, USC)
- American Lung Association
- NIH [AI139386, AI143870]
- Quintin Hogg Foundation
- Company of Biologists, Biochemical Society
- University of Westminster
Unlike other bacteria, Mycobacterium tuberculosis has the ability to utilize host fatty acids as a carbon source, which contributes to its pathogenicity and drug tolerance. Identifying key enzymes involved in fatty acid metabolism is important for new drug development. Recent research has shown a link between fatty acid-induced dormancy-like state and drug tolerance via dysregulated MCC activity.
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.
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