SBIR-STTR Award

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.

The antibacterial drug thiostrepton binds to the L11 binding site of the 23S rRNA in bacterial ribosomes and prevents protein synthesis, yet is clinically unattractive due to poor pharmacokinetic properties. We have discovered in our Phase I work a number of compounds that work by a mechanism similar to that of thiostrepton. The related structural features of these compounds suggest that a compelling structure-- activity relationship (SAR) pattern can be uncovered by a directed analog synthesis effort. The Phase II grant proposes to prepare a large number of analogs of the previously discovered compounds for evaluation in a direct RNA binding assay, a cell-free translation assays, and MIC assays. The SAR of each series will then be analyzed using an automated analysis method, and a pharmacophore model will be constructed. This model will be used to predict a second generation series of compounds to prepare in order to maximize antibacterial activity. Compounds meeting the appropriate criteria for activity will be evaluated in animal models. This process will yield broad spectrum antibacterial agents unlikely to be affected by current drug resistance mechanisms, which will be exceedingly useful to the clinical market. PROPOSED COMMERCIAL APPLICATIONS: The development of disease-causing microorganisms resistant to many, if not all, of the currently available antimicrobial compounds has made it necessary to develop new classes of drugs. The discovery, in the Phase I portion of this work, of novel compounds acting against a proven, but clinically unused, drug target provides the opportunity to create a broad spectrum drug useful against a variety of clinical indications including drug resistant microorganisms.