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: 10557848
• 负责人: Maciej Walczak
• 金额: $ 30.25万
• 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/10557848
• 关键词: Acceleration; Anabolism; Anti-Bacterial Agents; Antibiotics; Azoles; Bacteremia; Behavior; Binding; Biological; Biology; Biophysics; Chemicals; Clinical Research; Data; Development; Discrimination; Disease; Drug Design; ESKAPE pathogens; Elements; Engraftment; Enzymes; Evaluation; Genes; Goals; Gram-Positive Bacteria; Health; Healthcare Systems; Human; Investigation; Knowledge; Lead; Light; Methods; Microbiology; Modality; 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-Activity Relationship; Tail; Testing; Therapeutic; Thiazoles; Treatment Protocols; Validation; antimicrobial; antimicrobial drug; antimicrobial peptide; antimicrobial resistant pathogen; aqueous; bacterial resistance; bactericide; bioactive natural products; biophysical analysis; candidate identification; catalyst; clinical investigation; combat; computer studies; covalent bond; dehydroalanine; design; drug discovery; economic cost; flexibility; improved; innovation; invention; member; methicillin resistant Staphylococcus aureus; mortality; novel; novel therapeutics; pathogen; pre-clinical; preclinical study; predictive modeling; resistant strain; small molecule; standard care; structural biology; timeline; tool; translational potential

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.

项目总结/文摘