Syntheses of Bactobolin and Acybolin Antibiotics for Biological Studies of Analogues

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PROJECT SUMMARY Since the commercialization of penicillin in 1928, antibiotics have been hailed as “magic bullets”. In recent years, however, the number of bacterial strains resistant to clinically used antibiotics has sharply increased. The lack of viable first-line treatments of these bacterial infections has forced clinicians to consider second-line antibiotic options such as polymyxins and aminoglycosides, traditionally avoided because of significant toxicity. Thus, the development of antibiotics with new mechanisms of action for the control of pernicious bacterial infections is of vital importance. The synthesis of natural products and simplified derivatives has been a particularly successful strategy for the enrichment of the anti-bacterial armamentarium. The specific aims of this proposal are: 1. Completion of the first enantiospecific synthesis of Acybolin A and the second enantiospecific synthesis of Bactobolins A-B. Bactobolins A-B are two broad spectrum natural product antibiotics whose mechanism of action is the inhibition of protein translation via binding to an unprecedented site of the 50S ribosomal subunit and displacing tRNA bound at the P site. Acybolin A is a recently isolated antibiotic which shares strong structural homology to the Bactobolins but, excitingly, retains antibiotic activity against Bactobolin-resistant strains of B. subtilis. The biological basis underlying such disparate activity remains unknown. 2. Generation and evaluation of a plethora of functional analogues for future medicinal chemistry efforts. The rationale for this proposed research is that its success would allow for access to a diverse collection of antibacterial compounds with modes of action that are likely mechanistically distinct from FDA- approved antibiotics. The expected outcome of this research is the completion of several important steps towards the timely development of new, broad-spectrum, tolerable antibiotics and probe compounds for microbiological studies. The successful execution of the research proposed herein is expected to have a significant positive impact by aiding the global effort to reduce human morbidity and mortality resulting from pernicious bacterial infections.