Grant: Project Grant

Mycobacterium tuberculosis (Mtb) causes the devastating lung disease tuberculosis (TB). Nearly two million people die from TB annually. Mtb infects and grows inside macrophages, a type of white blood cell, present in the lungs of patients. Within these human cells, the bacteria are hidden from the host immune response and are protected from drug therapy, thus creating challenges for anti-TB drug discovery. With the increasing prevalence of multidrug and extensively drug resistant tuberculosis in multiple countries, there is a pressing need for new approaches to combat TB. In this proposal, we apply our knowledge for novel drug discovery and offer a unique approach towards studying enzymes and proteins that control the lifestyle of Mtb hidden within human macrophages that are affected by these potential new drugs. Using compounds that we previously identified to inhibit Mtb growth in macrophages, we will (a) identify proteins that bind to these compounds, and (b) select for Mtb mutants that are resistant against these compounds. Both approaches allow the identification of new drug targets either in the bacterium or in the host macrophages. In addition, our studies yield novel information about microbial biology and the means by which bacteria are able to successfully infect and reside within the human host.