A long-standing research interest of the Garcia lab has been the biosynthesis and physiological roles of modified bases in RNA. More recently we have shifted our focus to antibiotic discovery in two areas. Tuberculosis is a global human health problem of staggering proportions, causing nearly 1.4 million deaths in 2011. Current TB drugs require up to nine months of treatment and poor compliance promotes the emergence of drug-resistant strains. We are using a structure-based approach to discover improved RNAP inhibitors in collaboration with the Showalter lab here at UM and the Murakami lab at Penn State. Shigella flexneri is a human enteropathogen that infects ca. 165 million people and claims more than 1 million lives per year worldwide. Targeting Shigella virulence pathways is attractive because such drugs would be expected to exhibit less emergence of drug resistance and have no effect on normal colonic microbiota. We have successfully conducted high-throughput screens of ~142,000 compounds and ~20,000 natural product extracts against VirF, which initiates expression of the key Shigella virulence genes. We are characterizing the hits which block VirF activity in collaboration with the Sherman lab here at UM and the Maurelli lab at USUHS in Maryland. You can learn more about each of these projects by following the links under Research.
Our research has been supported by: the National Science Foundation; the National Institutes of Health; and the College of Pharmacy, Horace H. Rackham Graduate School, and Office of the Vice-President for Research of the University of Michigan.