Studies of KshAB, a cholesterol-degrading oxygenase from Mycobacterium tuberculosis

Tuberculosis kills more than two million people worldwide every year. More than one-third of the world’s population is currently infected with Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis. Because of its synergy with HIV infection, TB is the leading cause of death in HIV-infected individuals. Contributing to this global health crisis is the emergence of multi-drug resistant strains (MDR-TB), including extensive drug resistant strains (XDR-TB). The drug course to clear MDR-TB lasts up to two years, and XDR-TB is virtually untreatable with current therapies. These factors, combined with the high toxicities of current drugs, underline the urgent need for novel therapeutics to combat this disease. One of the major contributing factors to the prevalence and persistence of the disease is the bacterium's ability to survive within the human macrophage, a type of scavenger cell that normally combats disease-causing bacteria. The mechanisms by which Mtb survives inside the macrophage in the immune system are largely unknown. However, a set of genes that encode (produce) a series of cholesterol-degrading enzymes in Mtb has recently been discovered as essential to the bacterium’s survival. Compounds that inhibit Mtb’s cholesterol-degrading enzymes might be useful starting points for the design of novel therapeutics. Jenna Capyk is focusing on one of these cholesterol-degrading enzymes, known as KshA. She is studying how this enzyme works and how it is inhibited by small molecules. Her work also involves determining KshA’s three-dimensional structure and synthesizing potential inhibitors for the enzyme. By investigating the mechanisms of this promising new enzyme target in tuberculosis, Capyk’s studies may help lay the foundation for the development of new classes of therapeutics to treat this deadly disease.