Synthesis and Chemical Biology of Thiopeptide Antibiotics

项目摘要/摘要 抗生素已经改变了人类的健康和疾病格局。然而，使用和 滥用这类抗菌药物加速了耐药菌株的出现 对抗抗生素，因此标准的治疗方案最终变得无效。根据…… 这些关键的需求，硫肽已经成为一个有希望的平台，以发现 新的治疗线索。在目标1中，我们将开发和优化26个成员的制备 通过发明一种新的环状脱水方法来方便硫代多肽的合成。 在这一目标中确立的方法将在有代表性的情况下得到验证 含唑/唑啉的抗菌肽。在目标2中，我们将优化一个精简的 钼催化环脱水合成35元硫多肽的研究 选择性DHA突变。这些发现将释放以前的 一类未被开发的强效抗生素。在目标3中，我们将开发一个自动化平台，用于 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希望的线索 调查。上述目标的成功实现将建立创新工具 用于合成硫肽和其他具有生物活性的大环肽。因为 氮酮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，这项研究的发现将对 开发新的治疗方法。

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.