Metabolomics

Dataset Information

1

Multiple acyl-coA dehydrogenase deficiency kills Mycobacterium tuberculosis in vitro and during infection


ABSTRACT:

The human pathogen Mycobacterium tuberculosis (Mtb) devotes a significant fraction of its genome to fatty acid metabolism. Although Mtb depends on host fatty acids as a carbon source, fatty acid b-oxidation is mediated by genetically redundant enzymes, which has hampered the development of antitubercular drugs targeting this metabolic pathway. Here, we identify rv0338c, referred to as etfDMtb, to encode a membrane dehydrogenase essential for fatty acid b-oxidation in Mtb. An etfD deletion mutant (DetfD) was incapable of growing on fatty acids in vitro, with long-chain fatty acids being bactericidal, and failed to grow and survive in mice. The DetfD metabolome revealed a block in b-oxidation at the step catalyzed by acyl-CoA dehydrogenases (ACADs). In many organisms, including humans, ACADs are functionally dependent on an electron transfer flavoprotein (ETF) and cognate dehydrogenase. Immunoprecipitation identified EtfD in complex with FixA (EtfBMtb). FixA (EtfBMtb) and FixB (EtfAMtb) are homologous to the human ETF subunits. Our results demonstrate that EtfBAMtb constitutes Mtb’s ETF, while EtfDMtb, although not homologous to human EtfD, functions as the dehydrogenase. These findings identify Mtb’s fatty acid b-oxidation as a novel potential target for TB drug development.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase

SUBMITTER: Robert Jansen  

PROVIDER: MTBLS2374 | MetaboLights | 2021-09-29

REPOSITORIES: MetaboLights

Dataset's files

Source:
Action DRS
MTBLS2374 Other
DERIVED_FILES Other
Experiment 1 Other
Comp-T24-13C-But-IP-1.mzXML Mzxml
Comp-T24-13C-But-IP-2.mzXML Mzxml
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