The eubacterial signal recognition particle, comprised of a 4.5S RNA and protein P48, will be explored as a new class of target for rationally designed small-molecule antimicrobial compounds. Compounds from the Available Chemicals Directory and Isis Pharmaceuticals libraries will be docked against the RNA structures, and scored and ranked for quality of fit using molecular modeling. The lowest scoring 20000 compounds will be screened for their ability to disrupt the RNA-protein interaction in a scintillation proximity-based high through-put screen. The most active compounds will be selected for structure-activity studies and further synthetic elaboration in Phase II.
New classes of antimicrobial compounds are needed to offset developing drug resistance. Identification and development of new orally bioavailable agents against a conserved RNA target in bacteria would generate a significatmarket opportunity. Therapeutic target organisms could include pneumococci, enterococci, and tuberculosis - especially their drug-resistant strains.
