Grant: Project Grant

Mycobacteria cause a number of serious diseases. For example, more people die of tuberculosis (TB) each year than any other infectious disease other than Covid. The bacterium that causes the disease, Mycobacterium tuberculosis (Mtb), infects one third of all people world-wide. With the rise of drug resistant strains and co-infection with HIV, TB remains a global health emergency. In Canada, TB is of particular concern in the First Nations. The treatment of even drug-sensitive TB is arduous, with patients taking a cocktail of toxic chemotherapeutics for six months. Novel therapies are urgently needed to decrease the length, and improve the efficacy, of treatment. A related bacterial strain, Mycobacterium abscessus (Mab), is responsible for pulmonary infections often associated with Cystic Fibrosis (CF). Mab is intrinsically drug resistant, complicating treatment of infections, and the global incidence of Mab infections is rising. Thus, novel therapies are also required to treat Mab infections. We discovered a pathway in Mtb that enables the pathogen to grow on cholesterol during infection. This pathway has become a target for novel drugs to treat TB. We recently demonstrated that Mab has a similar pathway to grow on cholesterol, and that the bacterium appears to also use cholesterol during infection. Nevertheless, there are many aspects of Mtb's and Mab's abilities to degrade cholesterol that are not yet known. The overall objective of this project is to better understand Mtb's and Mab's cholesterol degradation pathway, including how this pathway works and how it enables these bacteria to be such pernicious pathogens. Improved understanding of the pathway will facilitate the development of novel drugs urgently needed to combat the diseases caused by these pathogens.