基于Teixobactin的新型抗耐药菌及抗耐药结核病药物研究

Infectious disease is one of the greatest threats to public health. Serious resistance of antibiotics and anti-tuberculosis drugs caused by excessive use or abuse of antibiotics and anti-tuberculosis drugs have resulted severe challenges to clinical treatment, especially for multi-drug resistant M. tuberculosis. Therefore, it is urgent to find new-mechanism-based antibiotics and anti-tuberculosis drugs without potential resistance. In this study, we will construct a novel polypeptide library based on teixobactin through the establishment of synthetic route, rational drug modification and exploration of the structure-activity relationship by extensive activity evaluation. The mechanism of teixobactin analogues will be elucidated through NMR technique. Starting from SAR and molecular mechanism studies, lead compounds will be further optimized to develop low toxic and effective antibiotics and anti-tuberculosis drug. Our preliminary study has established reasonable synthetic routes, evaluation methods and a few promising analogs, which will lay a solid foundation for the development of novel antibiotics and anti-tuberculosis drugs with clear mechanism and without resistance.

感染性疾病是当前世界公众健康最大威胁之一。抗生素和抗结核药物的广泛使用甚至滥用导致了多耐药菌及多耐药结核杆菌的加速产生。如何发现新颖结构的无耐药性抗耐药菌和抗耐药结核药物迫在眉睫。本研究以新型无耐药性的天然产物teixobactin为基础，通过建立合成路线、合理化结构修饰，构建新型多肽类化合物库，由活性评价结果探究构效关系，同时通过核磁技术阐明活性分子与药物靶点lipid II之间的相互作用机制。基于构效关系和机制进行结构再优化力争得到低毒、高效的新型抗耐药菌及抗耐药结核先导化合物。本项目初期的合成路线建立、相应生物学评价体系的构建、活性与teixobactin相当的衍生物的发现、分子机制的初步研究结果，将为后期开发新型、机制明确的抗耐药菌及抗耐药结核药物奠定坚实基础。

感染性疾病仍是目前全球公众健康领域的一个最大威胁。抗生素和抗结核药物的广泛使用导致了多重耐药病原菌如革兰氏阳性菌及多耐药结核杆菌的产生。所以发现具有新颖结构及新颖作用机制的不易产生耐药性的抗耐药菌和抗耐药结核药物极为重要。本项目以新型无耐药性的天然产物teixobactin为基础，通过建立合成路线、合理化结构修饰，构建新型多肽类天然产物化合物库，由活性评价结果探究构效关系，同时通过核磁技术阐明活性分子与药物靶点lipid II之间的相互作用机制。基于构效关系和机制研究开展进一步的结构优化，来获取低毒、高效的新型抗耐药菌及抗耐药结核先导化合物。本项目通过高效快速合成路线的建立、相应生物学评价体系的构建、活性与teixobactin相当的衍生物的发现、分子机制的研究结果，将为未来开发新型、机制明确的抗耐药菌及抗耐药结核药物奠定坚实基础。.当的衍生物的发现、分子机制的初步研究结果，将为后期开发新型、机制明确的抗耐药菌.及抗耐药结核药物奠定坚实基础。