Despite years of research, tuberculosis remains a leading killer, causing almost two million deaths each year worldwide. While the treatment for drug-sensitive disease is effective, it requires supervised therapy for extended periods of time and remains difficult to implement in the developing world that is disproportionately affected. Multidrug resistant disease can be impossible to treat.

We are using genetic and proteomic methods to study the causative organism of tuberculosis, Mycobacterium tuberculosis. Our research has two goals. First, we would like to understand the molecular details of pathogenesis in this bacterium. To do this, we have defined the bacterial genes required for survival during infection of macrophages or mice but not for in vitro growth. These have revealed several clues about how this pathogen interacts with the host. We are using this information to specifically probe the functions of these virulence genes, most of which cannot be determined by simple sequence analysis.

We are also trying to improve drug therapy for tuberculosis. Many of the antibiotics used to treat tuberculosis are unique and are used in few other infections. We are trying to define the mechanism of action of some of these drugs and understand how bacteria become resistant. We have also defined the set of genes required for optimal in vitro growth of M. tuberculosis and are using genetic, biochemical and small molecule methods to help determine the functions of many of these genes.

We are also studying a second pathogen, Francisella tularensis, the cause of tularemia. This zoonotic disease bears several similarities to tuberculosis even though it is caused by an entirely unrelated bacterium. The genetics of this organism are much less well developed than for many other gram negative bacteria. We are working out techniques to create mutant strains of F. tularensis that will allow us apply many of the tools we use in our study of tuberculosis to tularemia.