Clinical Microbiology: Open Access

Catabolism of cholesterol rings C and D by Mycobacterium tuberculosis

4^th International Conference on Clinical Microbiology and Microbial Genomics

October 05-07, 2015 Philadelphia, USA

Israel Casabon

The University of British Columbia, Canada

Posters-Accepted Abstracts: Clin Microbiol

Abstract:

Cholesterol catabolism is critical for Mycobacterium tuberculosis (Mtb) virulence. However, many aspects of this catabolism remain unknown. In Mtb and related Actinobacteria, the cholesterol side chain and rings A and B are degraded to yield 3aα-H- 4α (3�??-propanoate)-7aα-methylhexahydro-1,5-indanedione (HIP), a metabolite that contains steroid rings C and D. HIP catabolism is initiated by thioesterification to HIP-CoA and appears to be specified by the enzymes encoded by the KstR2 regulon. The KstR2 regulon of Mtb is up-regulated during growth on HIP and contains several genes encoding putative β-oxidation-type enzymes, ipdAB, and Rv3553. Both ipdAB and Rv3553 are essential for cholesterol catabolism by Mtb, but only ipdA appears to be essential for its survival in infection models. A �?ipdAB mutant of Mtb was slowly killed when incubated with cholesterol, and did not grow on glycerol in presence of cholesterol, suggesting it accumulated bacterio-toxic metabolites. Furthermore, deletion of ipdAB and ro04649, the ortholog of Rv3553, in Rhodococcus jostii RHA1 (RHA1) abrogated growth on cholesterol and HIP, and significantly delayed growth when these strains were incubated in presence of HIP and a second carbon source, suggesting generation of toxic metabolites from HIP. Similar results were obtained by deleting other KstR2-regulated genes in Mycobacterium smegmatis. Using LCMS-based metabolite profiling, we identified a number of previously undescribed cholesterol-derived CoA thioesters in deletion mutants. Some of these were characterized as ring C-opened metabolites. Altogether, these results allow us to suggest specific roles for several KstR2-encoded enzymes and to propose a model for HIP catabolism in Mtb.

Biography :

Email: israelcasabon@hotmail.com