Syntheses of Bactobolin and Acybolin Antibiotics for Biological Studies of Analogues

项目总结 自1928年青霉素商业化以来，抗生素一直被誉为“灵丹妙药”。在最近 然而，多年来，对临床使用的抗生素产生抗药性的细菌菌株数量急剧增加。这个 这些细菌感染缺乏可行的一线治疗方法，迫使临床医生考虑二线治疗。 抗生素选择，如多粘菌素和氨基糖苷类，传统上是避免的，因为有显著的毒性。 因此，开发具有新的作用机制的抗生素来控制有害细菌 感染是至关重要的。天然产物和简化衍生物的合成已经成为一种 尤其成功的战略是浓缩抗菌武器。这样做的具体目的是 建议：1.完成第一次对映异构体的合成和第二次对映体合成 芽孢杆菌菌素A-B的对映专一性合成杆菌素A-B是两种广谱天然产物 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 50S核糖体亚基的改变，取代结合在P位的tRNA。Acybolin A是一种最近分离出来的抗生素 它在结构上与杆菌素有很强的同源性，但令人兴奋的是，它保留了对 枯草芽孢杆菌的抗菌素菌株。这种不同活动背后的生物学基础仍然存在 未知。2.为未来的药物开发大量的功能类似物 化学方面的努力。这项拟议研究的基本原理是，它的成功将允许获得不同的 具有可能在机制上与FDA不同的作用模式的抗菌化合物的集合- 批准的抗生素。这项研究的预期结果是完成以下几个重要步骤 及时开发新的、广谱、耐受的抗生素和微生物探针化合物 学习。本文提出的研究的成功实施预计将具有重大的积极意义 通过协助全球努力减少由有害细菌引起的人类发病率和死亡率而产生的影响 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.