Syntheses of Bactobolin and Acybolin Antibiotics for Biological Studies of Analogues

项目摘要 自1928年青霉素商品化以来，抗生素一直被誉为“灵丹妙药”。近几 然而，近年来，对临床使用的抗生素具有耐药性的细菌菌株的数量急剧增加。的 缺乏可行的一线治疗这些细菌感染迫使临床医生考虑二线 抗生素的选择，如多粘菌素和氨基糖苷类，传统上避免，因为显着的毒性。 因此，开发具有新作用机制的抗生素用于控制有害细菌 感染至关重要。天然产物和简化衍生物的合成一直是一个重要的研究领域。 这是一个特别成功的抗菌医疗设备富集策略。具体目标是 建议如下：1.完成Acybolin A的第一次对映体特异性合成和Acybolin A的第二次对映体特异性合成。 Bactobolins A-B的对映体特异性合成。Bactobolins A-B是两种广谱的天然产物 其作用机制是通过与前所未有的位点结合来抑制蛋白质翻译的抗生素 50 S核糖体亚基的结合，并取代结合在P位点的tRNA。Acybolin A是最近分离的抗生素 它与Bactobolins具有很强的结构同源性，但令人兴奋的是，它保留了对 B.枯草杆菌。这种完全不同的活动背后的生物学基础仍然存在 未知2.用于未来药物的大量功能类似物的产生和评价 化学努力。这项拟议研究的理由是，它的成功将允许获得多样化的 抗菌化合物的集合，其作用机制可能与FDA不同- 批准的抗生素。这项研究的预期成果是完成几个重要步骤， 及时开发新的、广谱的、耐受的抗生素和微生物探针化合物， 问题研究本文提出的研究的成功执行，预计将有重大的积极意义。 通过帮助全球努力减少由有害细菌引起的人类发病率和死亡率， 感染.

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.