Synthesis and Chemical Biology of Thiopeptide Antibiotics

项目概要/摘要 抗生素改变了人类健康和疾病的面貌。然而，使用和 滥用这类抗菌药物会加速耐药菌株的出现 因此，标准治疗方案最终变得无效。鉴于 这些关键的需求，硫肽已经成为一个有前途的平台，发现 新的治疗方法在目标1中，我们将开发和优化26元的制备方法， 硫肽通过发明一种新的环化脱水方法来促进合成运动。 在此目标中建立的方法将在代表性的背景下进行验证。 含有唑/唑啉的抗微生物肽。在目标2中，我们将优化一个精简的 钼催化环化脱水和位阻法合成35元硫肽 选择性Dha突变。这些发现将释放以前的翻译潜力， 一种尚未开发的强效抗生素在目标3中，我们将开发一个自动化平台， 合理的硫肽设计和修饰，并将其与微生物，生物物理， 和计算研究，以产生适用于临床前和临床的有前途的线索， 调查事务所成功实现上述目标将建立创新工具， 用于合成硫肽和其他生物活性大环肽。因为 唑类化合物作为生物活性天然产物中关键结构元素的重要性 生物医学的相关性，这项研究的发现将产生变革性的影响， 开发新的疗法。

PROJECT SUMMARY/ABSTRACT Antibiotics have transformed the human health and disease landscape. However, the use and misuse of such antimicrobial drugs accelerate the emergence of bacterial strains resistant against antibiotics, so that standard treatment options eventually become ineffective. In light of these critical needs, thiopeptides have emerged as a promising platform for the discovery of new therapeutic leads. In Aim 1, we will develop and optimize the preparation of 26-membered thiopeptides by inventing a new cyclodehydration methods to facilitate the synthetic campaign. The methods established in this aim will be validated in the context of representative azole/azoline-containing antimicrobial peptides. In Aim 2, we will optimize a streamlined synthesis of 35-membered thiopeptides by integrating Mo-catalyzed cyclodehydrations and site- selective Dha mutations. These findings will unlock the translational potential of a previously unexplored class of potent antibiotics. In Aim 3, we will develop an automated platform for rational thiopeptide design and modifications, and integrate it with microbiological, biophysical, and computational studies to generate promising leads suitable for pre-clinical and clinical investigations. Successful realization of the abovementioned aims will establish innovative tools for the synthesis of thiopeptides and other bioactive macrocyclic peptides. Because of the importance of azol(in)es as the key structural elements in bioactive natural products of biomedical relevance, the discoveries of this study will have a transformative impact on the development of new therapies.