Cholesterol Metabolism In Mycobacterium Tuberculosis: Chewing Through The Fat

New drugs with novel mechanisms of action are required to meet the severe threat to human health posed by the emergence of drug resistant strains of M. tuberculosis (M. tb). M. tb imports and metabolizes host cholesterol during infection, which is critical for the maintenance of M. tb infection. Both the igr operon and fadA5 are required for in vitro growth using cholesterol as a sole carbon source and for full virulence of M. tb in the mouse model of in vivo infection. We have elucidated the function of these genes, their corresponding enzymes and their role in cholesterol metabolism using a combination of transcriptional profiling, bioinformatics, enzymology, biochemistry and metabolic phenotype screening. The 2’propanoyl CoA side chain cleavage intermediate undergoes β‐oxidation catalyzed by FadE28/29, a heterotetrameric acyl CoA dehydrogenase, and Rv3542c/3541c, a heterotetrameric enoyl CoA hydratase; both are encoded by the igr operon. FadA5 is a thiolase that catalyzes side chain cleavage. Ultimately, drug discovery targeting these enzymes will provide inhibitors that attenuate M. tb growth and persistence in vivo. NIH ( AI065251 , AI092455 , HL53306, S10RR021008 to NSS, A1044856, AI065987 to IS, DK007521 to NMN R01AI067027 to DGR) DOE‐GAANN to STT