Wednesday, December 12, 2012
Organic Chemistry Seminar
Chemical Probes to Explore and Inhibit Bacterial Growth and Pathogenesis
Erin E. Carlson, Assistant Professor, Chemistry Department, Indiana University
Given the dearth of new antibacterial drugs and the facile evolution of microbial resistance, some fear that we have entered the "post-antibiotic era." Our research focuses on both the development and application of new technologies to explore the mechanisms of bacterial growth and pathogenesis and the identification of potential therapeutic agents. We are particularly interested in generating tools for the study of two-component signal transduction systems (TCSs), which are commonly used by bacteria to couple environmental stimuli to adaptive responses through gene regulation. They contribute to many critical bacterial functions, including virulence, resistance mechanisms, and survival, making the TCS proteins potential drug targets. The high degree of homology in the ATP-binding site of histidine kinases, a critical player in TCSs, suggests that appropriately designed compounds could serve as probes for the global profiling of TCS activities. Progress towards this goal will be discussed.
Despite the urgent need for the development of antibiotics, only three new classes of drugs have been introduced in the last four decades. To facilitate the discovery of antibacterial agents, such as TCS inhibitors, we are also devising new strategies for natural products isolation. Despite recent advances, the identification of novel natural products remains challenging as the use of traditional isolation methods often results in rediscovery of known compounds and/or the loss of bioactivity. Current enrichment strategies employed in natural products discovery still rely on relatively crude extraction and/or chromatographic separation techniques. To produce an enrichment strategy that provides a significant improvement over these techniques, a method that employs enrichment principles that are independent of the physicochemical properties of the compounds must be devised. We are creating a toolkit of functional group-specific tags to facilitate compound isolation and advance the exploration of natural product chemical space. To accomplish this goal, we employ controllably reversible reactions to immobilize the targeted functional group class onto solid support. Enriched natural products are then released using "traceless" conditions for direct characterization. Development and application of tagging strategies that facilitate the chemoselective enrichment of hydroxyl-, phenol-, and carboxylic acid-containing natural products will be discussed. Together, the described studies will lead to a more comprehensive understanding of bacterial development and pathogenesis and may provide novel therapeutic targets and lead structures.