B-212. A Chemical Genetic Approach to Dissecting Virulence Pathways in M. tuberculosis

S. A. Stanley, J. Aquadro, M. Vokes, A. Carpenter, D. Hung;
Massachusetts Inst. of Technology, Cambridge, MA.

Mycobacterium tuberculosis is one of the worlds most significant and devastating pathogens. One-third of humanity is infected with M. tuberculosis, and 2 million deaths are attributable to this disease annually. A major barrier to the eradication of M. tuberculosis is the difficulty of treatment, which requires prolonged therapy with multiple antibiotics. In addition, drug resistance is becoming a major problem, with strains of M. tuberculosis arising that are resistant to every known effective antibiotic. For the development of new pharmaceuticals, a better understanding of the molecular mechanisms of virulence is required. Here we describe a new approach to the analysis of M. tuberculosis virulence, in which small molecules are used to probe gene function in vivo. We have developed a macrophage infection model where growth and trafficking of M. tuberculosis are monitored using high content microscopy and automated image analysis. We have identified small molecules that inhibit growth of M. tuberculosis in macrophages, thereby identifiying novel pathways required for virulence.