Tethered aza-Wacker Technology for Complex Antibiotic Assembly

用于复杂抗生素组装的系链氮杂瓦克技术

• 批准号: 10272837
• 负责人: Shyam Sathyamoorthi
• 金额: $ 37.34万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10272837
• 关键词: Alkenes; Amination; Aminoglycosides; Anti-Bacterial Agents; Antibiotics; Area; Bacillus subtilis; Bacterial Infections; Bacterial Proteins; Binding; Biological; Chemicals; Clinical; Complex; Crystallization; Cyclization; Development; Family; Laboratories; Methodology; Methods; Natural Products; Organism; Outcome; Pathogenicity; Patients; Physicians; Polymyxins; Pseudomonas; Publishing; Reaction; Research; Risk; Site; Structure; Technology; Therapeutic; Time; Toxic effect; Translations; Work; analog; antibiotic design; antibiotic resistant infections; chemical synthesis; clinically relevant; functional group; human morbidity; human mortality; innovation; programs; resistant strain; sulfamate

Project Summary The number of bacterial strains resistant to clinically used antibiotics continues to increase at a frightening pace, and 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. Such reserve antibiotics often carry the risk of significant toxicity and subsequent patient harm. Thus, the timely development of new antibacterial agents, preferably with modes of action distinct from ones currently employed, is essential for the global decrease of human morbidity and mortality. The chemical synthesis of known antibacterial natural products is a strategy that has yielded great dividends in the past and continues to furnish important clinical therapeutics in the present. Often, while entrenched in the construction of such complex molecules, the synthetic practitioner is confronted by the limitations of available technology. Thus, the development of new organic methodology is often intimately joined with the pursuit of biologically-active natural products. The overarching themes guiding this R35 proposal are the development of new tethered aza-Wacker cyclization reactions and their use in the synthesis of nitrogenous antibiotics. The importance of a tethered reaction is that it frees the synthetic practitioner from the constraint of needing a pre-existing C–N bond in order to forge a new one, and our laboratory has published several studies in this area. We plan to apply this technology for the synthesis of the unusual dichlorinated polyketide antibiotics Bactobolins A-B and Acybolin A. Bactobolins A and B were first isolated from the culture broth of Pseudomonas yoshidomiensis and have been demonstrated to have broad antibacterial activity against a variety of pathogenic gram-positive and gram-negative organisms. Recent work has pinpointed the antibacterial activity of Bactobolin A to inhibition of bacterial protein translation via binding to an unprecedented site on the 50s prokaryotic subunit (L2); a crystal structure exists showing this interaction. Despite their rich biological activity, there exists only one racemic synthesis (Weinreb) and one enantiospecific synthesis (Švenda) of Bactobolin A. Acybolin A is a recently isolated antibiotic with activity against Bactobolin-resistant strains of B. subtilis, suggesting a disparate mode of action from Bactobolins despite structural homology. There currently exists no synthesis of the Acybolin family of natural products, no exploration of analogues, and limited analysis of biological activity. A key step in our proposed synthesis of these compounds is a reaction recently developed in our laboratory, the sulfamate aza-Wacker cyclization. The expected outcomes of this line of research include the development of powerful new methods for the site-selective amination of alkene moieties and access to a variety of new antibacterial compounds through precise stereocontrolled synthesis. Collectively, this work will establish a broad and robust program of synthetic chemical innovation and antibiotic design in my laboratory.

项目概要 对临床使用的抗生素产生耐药性的细菌菌株数量继续以惊人的速度增加， 由于缺乏针对这些细菌感染的可行的一线治疗方法，迫使我们考虑二线治疗 一线抗生素选择，例如多粘菌素和氨基糖苷类，此类储备抗生素通常会带来风险。 显着的毒性和随后的患者伤害因此，及时开发新的抗菌药物， 最好采取与目前所采用的行动方式不同的行动方式，对于全球减少 已知抗菌天然产物的化学合成是一种降低人类发病率和死亡率的策略。 过去已经产生了巨大的红利，并且现在继续提供重要的临床治疗。 通常，在构建如此复杂的分子时，合成实践者会面临 因此，新的有机方法的开发往往受到现有技术的限制。 结合对具有生物活性的天然产品的追求，指导 R35 提案的总体主题。 是新的束缚氮杂瓦克环化反应的开发及其在合成中的应用 含氮抗生素的重要性在于它使合成实践者摆脱了束缚。 需要预先存在的 C-N 键才能形成新的 C-N 键，我们的实验室已经发表了 我们计划将该技术应用于合成不常见的二氯化物。 聚酮化合物抗生素 Bactobolins A-B 和 Acybolin A。Bactobolins A 和 B 首先从培养物中分离出来 吉都假单胞菌肉汤，已被证明具有广泛的抗菌活性 最近的工作已经确定了多种致病性革兰氏阳性和革兰氏阴性生物体。 Bactobolin A 的抗菌活性通过与前所未有的结合来抑制细菌蛋白质翻译 50s 原核亚基 (L2) 上的位点；尽管它们具有丰富的相互作用，但存在显示这种相互作用的晶体结构。 生物活性，仅存在一种种族合成（Weinreb）和一种对映特异性合成（Švenda） Acybolin A 是最近分离出的一种抗生素，具有对抗 Bactobolin 耐药菌株的活性。 尽管目前存在结构同源性，但表明与 Bactobolins 具有不同的作用模式。 不存在 Acybolin 天然产物家族的合成，没有类似物的探索，且分析有限 我们提出的这些化合物合成的关键步骤是最近开发的反应。 在我们的实验室中，氨基磺酸氮杂瓦克环化这一系列研究的预期结果包括 开发用于烯烃部分的位点选择性胺化的强大新方法并获得 总的来说，这项工作将通过精确的立体控制合成来合成多种新型抗菌化合物。 在我的实验室建立一个广泛而强大的合成化学创新和抗生素设计计划。