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.
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.
| Jefferson, Elizabeth A; Seth, Punit P; Robinson, Dale E et al. (2004) Optimizing the antibacterial activity of a lead structure discovered by ""SAR by MS"" technology. Bioorg Med Chem Lett 14:5257-61 |
