Research Project
2777500
The conserved eubacterial interaction between 4.5S RNA and protein P48 will be explored as a target for rationally designed small-molecule antimicrobial compounds. The structure of an RNA constituting the P48-binding site in domain IV of 4.5S RNA will be determined using high-resolution NMR spectroscopy. These structures will be used as targets for docking ca. 2X105 compounds from the Available Chemicals Directory and Isis Pharmaceuticals libraries. The compounds will be scored and ranked for quality of fit using molecular modeling. Groups of the lowest scoring 2000 compounds will be screened for their ability to disrupt the RNA-protein interaction in a scintillation proximity-based system. Ten prototype scaffolds will be selected for subsequent synthetic elaboration in Phase II. PROPOSED COMMERCIAL APPLICATION New families of antimicrobial compounds are needed to offset developing drug resistance. Identification and development of a new class of antimicrobial compounds based on a conserved RNA target would generate a significant market opportunity. Therapeutic targets could include pneumococci, enterococci, and tuberculosis - especially their drug-resistant strains.
