基于环肽抗生素lugdunin的全新抗菌多肽的设计、合成及抗菌活性研究

Lugdunin是人体共生菌S. lugdunensis产生的新结构环肽抗生素。Lug-5K是我们发现的一个由lugdunin衍生的新结构肽醛，同lugdunin一样，对包括耐甲氧西林金黄色葡萄球菌、耐万古霉素粪肠球菌等在内的病原菌具有很强的抗菌活性，且溶血活性、细胞毒性低，极有潜力发展成为新型抗菌药物。本项目拟通过末端修饰、赖氨酸扫描、净电荷改变、碱性氨基酸侧链、官能团变化、氨基酸立体异构转换等策略设计合成一系列lug-5K的衍生物，通过抗菌活性、理化性质、空间结构研究，初步阐明构效关系并筛选出具有成药潜力的前导分子；然后通过进一步药效学评价、毒理学、药代动力学研究、结构优化、作用机制研究，以期获得2-3个具有自主知识产权、临床应用潜力的候选药物进行临床前评价。在当前耐药菌问题日益严重而临床上缺乏新结构抗菌药物背景下，开展以lug-5K为先导分子的创新药物发现具有重要的理论意义和应用价值。

Lugdunin is a new structural cyclopeptide antibiotic produced by S. lugdunensis. Lug-5k is a new structure peptide aldehyde derived from lugdunin, which is first discovered by our group. Like lugdunin, it has potent antibacterial activity against refractory pathogens including methicillin-resistant Staphylococcus aureus and vancomycin resistant Enterococcus faecalis, and has low hemolytic activity and cytotoxicity. It has great potential to be developed as a new antibacterial drug. In the present project, we plan to design and synthesize a series of derivatives of lug-5k through terminal modification, lysine scanning, net charge change, basic amino acid side chain length, functional group change, amino acid stereoisomerization change and other strategies. Through the investigation of antibacterial activity, physical and chemical properties, and spatial structure of all the synthesized derivatives, we want to initially clarify the structure-activity relationship and screen out the leading molecules with potential for medicine. Then the antibacterial efficacy, toxicology, pharmacokinetics and action mechanism of the leading molecules would be further investigated. Through further structrure optimization, we anticipate to acquire 2-3 candidate antimicrobial molecules with independent intellectual property rights and clinical application potential for further clinical study. At present, the problem of drug-resistant bacteria is becoming more and more serious, and there is few antibiotics with novel structure in clinic. So it is of great theoretical significance and application value to develop innovative antibacterial drugs with lug-5K as the leading molecule.