Research Project
2865203
Due to the tremendous increase in drug resistance, we are quickly approaching a point at which the currently available set of antimicrobial compounds will be useless. This necessitates not only the development of new drugs, but, more importantly, new types of drugs with new drug targets. Drugs directed against RNA structures would be one such novel development. The 23S rRNA binding site of the bacterial protein L11 will be explored as a target of rationally designed small-molecule anti-microbial compounds. The naturally occurring antibiotic, thiostrepton, binds to the 23S rRNA, but this antibiotic is not readily usable in oral form and is difficult to modify synthetically. A large amount of structural information exists, and is currently being generated for the L11 binding site within the 23S rRNA and this information will be used to assemble an RNA model. Compounds from the Available Chemicals Directory and Isis Pharmaceuticals libraries will be docked against the resulting RNA structure, scored and ranked for quality of fit using molecular modeling. The best scoring 2-5000 compounds will be screened for activity on the RNA-protein interaction in high throughput assay. The most active compounds will be selected for structure-activity studies and further synthetic elaboration in Phase II. PROPOSED COMMERCIAL APPLICATIONS: New classes of antimicrobial compounds are needed to offset developing drug resistance. Identification and development of new orally bioavailable reagents against a conserved RNA target would generate a significant market opportunity. Therapeutic targets could include pneumococci, enterococci and tuberculosis, especially that drug resistant strain.
