Synthesis and Chemical Biology of Thiopeptide Antibiotics

硫肽类抗生素的合成及化学生物学

• 批准号: 10211882
• 负责人: Maciej Walczak
• 金额: $ 30.28万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211882
• 关键词: Anabolism; Anti-Bacterial Agents; Antibiotics; Azoles; Bacteremia; Behavior; Binding; Biology; Biophysics; Chemicals; Clinical Research; Data; Development; Discrimination; Disease; Drug Design; ESKAPE pathogens; Elements; Enzymes; Evaluation; Genes; Goals; Gram-Positive Bacteria; Health; Healthcare Systems; Human; In Vitro; Investigation; Knowledge; Lead; Light; Methods; Microbiology; Modification; Molecular Target; Multi-Drug Resistance; Mutation; Oxazoles; Peptides; Pharmaceutical Chemistry; Pharmacology; Preparation; Property; Proteins; Research; Resistance; Resistance development; Resistance profile; Ribosomes; Role; Site; Solubility; Source; Structure; Structure-Activity Relationship; Tail; Testing; Therapeutic; Thiazoles; TimeLine; Treatment Protocols; Validation; antimicrobial; antimicrobial drug; antimicrobial peptide; antimicrobial resistant pathogen; aqueous; bacterial resistance; bactericide; base; bioactive natural products; biophysical analysis; candidate identification; catalyst; clinical investigation; combat; computer studies; covalent bond; dehydroalanine; design; drug discovery; economic cost; flexibility; improved; in silico; innovation; methicillin resistant Staphylococcus aureus; mortality; novel; novel therapeutics; pathogen; pre-clinical; preclinical study; predictive modeling; resistant strain; small molecule; standard care; structural biology; tool

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.

项目摘要/摘要 抗生素改变了人类健康和疾病局势。但是，使用和 滥用这种抗菌药物会加速抗细菌菌株的出现 反对抗生素，因此标准治疗方案最终变得无效。鉴于 这些关键需求，硫代肽已成为发现的有前途的平台 新的治疗铅。在AIM 1中，我们将开发和优化26成员的准备 硫代肽通过发明一种新的环化学方法来促进合成运动。 此目标中建立的方法将在代表性的背景下进行验证 偶氮/二唑氨酸抗菌肽。在AIM 2中，我们将优化一个简化的 通过整合Mo催化的循环水合物和位点 - 选择性DHA突变。这些发现将解锁以前的翻译潜力 未开发的有效抗生素类。在AIM 3中，我们将开发一个自动平台 有理硫代肽设计和修饰，并将其与微生物，生物物理， 和计算研究以产生有希望的潜在客户，适用于临床前和临床 调查。成功实现上述目标将建立创新的工具 用于合成硫肽和其他生物活性大环肽。因为 偶氮（ON）ES作为生物活性天然产物的关键结构元素的重要性 生物医学相关性，这项研究的发现将对 开发新疗法。