Characterization of a dioxygenase and a hydrolase critical to persistence of Mycobacterium tuberculosis in the macrophage

Tuberculosis (TB) is a contagious illness of the respiratory system that is spread through coughing and sneezing. This chronic infectious disease is caused by a bacterial microorganism, Mycobacterium tuberculosis. This bacterium infects one in three people worldwide and claims the lives of two to three million people each year. The incidence of TB is on the rise due to the emergence of multi-drug resistant strains and escalating numbers of HIV-linked deaths. These alarming trends have led the World Health Organization to declare tuberculosis a global health emergency. Pathogenicity of this bacterium is due in part to its unusual ability to survive for long periods of time and to replicate in human immune cells. The mechanisms behind this persistence are poorly understood which is why Katherine Yam is investigating a number of genes essential to pathogenesis of M. tuberculosis. Studies recently revealed that some of these genes are involved in degradation of cholesterol — a source of energy for the bacterium during infection. Yam is studying two of these cholesterol-degrading enzymes, HsaC and HsaD, which help the bacterium survive in the human body. By designing inhibitors for these enzymes, the cholesterol-degrading pathway of M. tuberculosis can be blocked, which will reduce the bacterium’s ability to cause disease. These enzymes are excellent new targets for TB drug treatments as they are not targets of current drugs and thus will circumvent the problem of drug resistance in TB.