Institute for Advanced Pharmaceutical Sciences: Molecular Targets and Drug Screens to Combat Bioterrorism

摘要

Anthrax continues to be a major threat to our national security and economy. We used multiple approaches for the development of novel therapeutics. (1) We engineered three isogenic mutant E.coli strains to be used for HTS screening for selective and specific inhibitors of anthrax protein synthesis. (2) We developed 2 assays for quantitation of peptide self-assembly and showed that ACDs inhibit specific aggregation pathways. (3) We demonstrated that inhibitors of FabI exhibit broad spectrum of activity against a variety of pathogens, and started to develop additional enzymatic targets in the fatty acid biosynthetic pathway. (4) We developed synthetic schemes for series of Antibiotic A-33853 derivatives and improved the potency of the original A-33853 two-fold against B. anthracis, and demonstrated that these derivatives are effective against wide spectrum of pathogens, including L. donovani. (5) We have developed automated MIC assay that can be used to screen up to 100K compounds/day against bacteria, and identified three structural classes as potential lead scaffolds for future medicinal chemistry improvement.