Syntheses of Bactobolin and Acybolin Antibiotics for Biological Studies of Analogues

用于类似物生物学研究的 Bactobolin 和 Acybolin 抗生素的合成

基本信息

批准号：
10270504
负责人：
Shyam Sathyamoorthi
金额：
$ 20.98万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10270504
关键词：
Amination Amines Aminoglycosides Anti-Bacterial Agents Antibiotics Bacillus subtilis Bacterial Infections Bacterial Proteins Binding Biological Biology Burkholderia Chemicals Chemistry Clinical Collaborations Collection Communicable Diseases Crystallization Cyclization Data Development Docking Drug Kinetics Eukaryotic Cell Evaluation FDA approved Foundations Future Generations Goals Homologous Gene Infection Kansas Laboratories Libraries Magic Microbiology Natural Products Outcomes Research Parents Penicillins Pharmaceutical Chemistry Pilot Projects Polymyxins Property Protein Inhibition Pseudomonas Reporting Research Research Project Grants Ribosomes Route Site Structure Synthesis Chemistry Testing Therapeutic Time Toxic effect Transfer RNA Translations United States National Institutes of Health Universities Work analog assay development base commercialization cytotoxicity design flexibility human morbidity human mortality in silico resistant strain stereochemistry success

项目摘要

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.

项目摘要自1928年青霉素商业化以来，抗生素被誉为“魔术牛犬”。最近然而，几年来，抗临床使用抗生素的细菌菌株数量急剧增加。这这些细菌感染缺乏可行的一线治疗，迫使临床医生考虑二线抗生素选择，例如多聚霉菌素和氨基糖苷，传统上由于毒性而避免。这是用新的作用机理来控制有害细菌的抗生素的开发感染至关重要。天然产物和简化衍生物的合成已是特别成功的策略，以富集抗菌武术。这个特定的目的提案是：1。完成Acybolin A的第一个对映体合成和第二个 Bactobolins A-B的对映体合成。 Bactobolins A-B是两个广谱天然产品抗生素的作用机理是通过与前所未有的位点结合抑制蛋白质翻译 50S核糖体亚基和p位于p位点的tRNA的位移。 Acybolin A是最近分离的抗生素它与Bactobolins具有强大的结构同源性，但令人兴奋地保留了针对的抗生素活性枯草芽孢杆菌的抗性毒素菌株。这种不同活性的生物基础仍然存在未知。 2。对未来医学的众多功能类似物的生成和评估化学工作。这项拟议的研究的理由是，它的成功将允许进入潜水员采集具有机械作用模式的抗菌化合物，这些化合物可能在机械上与FDA-不同批准的抗生素。这项研究的预期结果是完成了几个重要步骤微生物学的新型，广谱，可耐受抗生素和探针化合物的及时开发研究。预计本文提出的研究的成功执行将具有显着的积极通过帮助全球努力降低有害细菌引起的人类发病率和死亡率的影响感染。