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Cholesterol catabolism in mycobacterium tuberculosis : studies in pathogenesis, regulation, and metabolic toxicity Kirstin, Brown Lee


Tuberculosis (TB), a disease caused by the airborne bacterial pathogen Mycobacterium tuberculosis (Mtb) claims the lives of ~1.3 million people every year. Control of Mtb has been hindered by the inefficiency of the current treatment for the disease, which involves several months on a multi-drug regimen with extensive side-effects. The ability of Mtb to enter a state of metabolic quiescence further complicates the development of antimycobacterial agents. During infection, Mtb relies on host-produced cholesterol as a source of carbon and energy. The essentiality of cholesterol catabolism for Mtb during infection has been repeatedly demonstrated and the pathway has thus emerged as a potential target for the development of new TB therapeutics. Catabolism of the cholesterol sidechain and rings A/B leads to the production of propionyl-CoA, pyruvate, and the rings C/D containing metabolite 3aα-H-4α(3'-propanoate)-7aβ-methylhexahydro-1,5-indanedione (HIP). Many of the enzymatic steps involved in the degradation of HIP yield CoA thioester metabolites, the accumulation of which have been shown to cause cholesterol-mediated toxicity in deletion mutants. The findings presented in Chapter 3.1 demonstrate that HIP catabolism is important for the pathogenesis of Mtb and that the cholesterol catabolic pathway is a valid drug target. Chapter 3.2 reveals a novel mechanism involved in the regulation of HIP catabolism in which the first enzyme in its catabolism is reversibly acetylated. In Chapter 3.3, I have shown that deletion of certain HIP catabolizing enzymes leads to the accumulation of cholesterol-derived CoA thioesters, sequestration and depletion of free CoA resulting in a toxic phenotype. These findings suggest that HIP catabolizing enzymes are intriguing candidates for the development of novel TB antibiotics. Together, these data build on previous studies and provide additional insights into cholesterol catabolism in Mtb.  

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