Grant: Operating Grant

Mycobacterium tuberculosis infects one third of the world's population and kills more people worldwide than any other bacterium. In Canada, this pathogen is a particular concern in First Nations communities. Tuberculosis (TB) has been labeled a global health emergency due to its association with AIDS and the emergence of multidrug-resistant strains including XDR-TB, which can be virtually untreatable with existing drugs. New antibiotics are urgently required to treat TB. Several years ago, we discovered a series of enzymes in M. tuberculosis that break down cholesterol. We and other researchers have since demonstrated that some of these enzymes are essential for virulence. Nevertheless, many aspects of how cholesterol is degraded and how this degradation contributes to the disease are unknown. We propose to build on our discovery by pursuing three aims: (1) elucidate the complete step-by-step pathway that M. tuberculosis use to degrade cholesterol; (2) investigate how key cholesterol degradation enzyme function; and (3) evaluate how cholesterol degradation contributes to virulence. Some of the cholesterol-degrading enzymes are exceptional drug targets: they are essential to the bacterium's survival, have no close human homologues, and are not targets of current drugs, thereby reducing problems of "cross-resistance". Thus, the proposed research will help us develop effective inhibitors, a crucial step in developing new TB drugs. We will use a variety of cutting-edge approaches to pursue our aims. Our unique knowledge base and resources position us to generate novel insights into the pathogenesis of the world's deadliest bacterium and into important classes of enzymes, as well as to develop promising lead compounds for novel therapeutics.