DEVELOPMENT OF A SCREEN FOR BACTERIAL RNASE P INHIBITORS

The need for novel antibiotics has never been greater. Infectious diseases are the third cause of death in the US, and their toll is increasing, with a 580/0 increase in mortality from 1980 to 1992. A large reason for this rise is the evolution and spread of antibiotic- resistant bacteria. We plan to combat this rise in antibiotic resistance by identifying inhibitors of novel bacterial targets to produce new classes of antibiotics. This research proposal entails the necessary first step to reach this objective. We have chosen to target the essential enzyme RNase P because of its unique characteristics that make it an excellent candidate for a program in antibiotic development. All organisms require RNase P to process precursors of tRNAs. Without its function, protein synthesis is blocked. The structure of RNase P is highly conserved among all bacteria, but is extremely divergent from humans, making it an ideal candidate for a target of a broad-spectrum, low-toxicity antibiotic. Phase 1 of our investigation will consist of developing, optimizing, and validating an assay for high-throughput screening of RNase P enzyme inhibitors. Subsequent phases will entail performing a high-throughput screen, characterizing inhibitors, identifying lead compounds, and developing these leads into IND candidates.