新型铁载体-单环β-内酰胺偶联体的设计、合成及抗多药耐药革兰氏阴性菌活性研究

Multidrug resistance, particularly among Gram-negative pathogens, represents a serious crisis to human health. There is nearly no effective therapeutic options for the treatment of infections caused by multidrug-resistant Gram-negative bacteria in clinic. Therefore, identifying and developing new antibacterial agents becomes urgently needed. Utilizing bacterial iron uptake mechanisms, this project will appropriately combine antibacterial agents with siderophore moiety together, which makes antibacterial agents delivered into periplasmic space in an active transport way when bacteria activate the siderophore transport system to uptake iron. This approach will overcome many common efflux and low permeability mutations. In this proposed project research, 80 novel siderophore-conjugated monocarbam will be designed and prepared, their structure-activity/metabolism/toxicity relationship will be thoroughly evaluated. We expect to obtain one or two promising candidates with high in vitro and in vivo potency against multidrug-resistant Gram-negative pathogens, excellent metabolic properties, low toxicity and good stability, which will lay a solid foundation for the development of new antibacterial agents. Meanwhile, two patents and two to four high quality articles will be published, four doctorial and graduate students will be trained during this project.

细菌耐药性特别是革兰氏阴性菌的耐药性已成为危害人类健康的重大公共卫生危机，目前临床上没有能安全有效治疗耐药性革兰氏阴性菌感染的药物，因此研发对耐药革兰氏阴性菌有效的药物迫在眉睫。本研究将利用细菌摄取铁的原理，将抗菌药物与铁载体巧妙的有机结合，使细菌在获取铁的同时，主动将抗生素和铁一起运输进体内，有效克服革兰氏阴性菌外膜难以通透的障碍，达到迅速杀死细菌的目的。本研究将设计、合成四个系列（详细正文）共计 80个左右新型铁载体-单环β-内酰胺偶联体，并深入研究其构效、构代和构毒关系，争取发现1-2个体内外对多药耐药革兰氏阴性菌高度有效、代谢性质优良、毒性低、稳定性好，具有开发前景的候选化合物，为最终开发出拥有我国自主知识产权的创新药物奠定坚实的知识基础。预计将申请专利 2 项，发表SCI研究论文 2-4 篇，培养4名以上硕士和博士研究生。

细菌耐药性特别是革兰氏阴性菌的耐药性已成为危害人类健康的重大公共卫生危机，目前临床上没有能安全有效治疗耐药性革兰氏阴性菌感染的药物，因此研发对耐药革兰氏阴性菌有效的药物迫在眉睫。本研究利用细菌摄取铁的原理，将抗菌药物与铁载体巧妙的有机结合，使细菌在获取铁的同时，主动将抗生素和铁一起运输进体内，有效克服革兰氏阴性菌外膜难以通透的障碍，达到迅速杀死细菌的目的。本研究将设计、合成70余个新型铁载体-单环β-内酰胺偶联体和7个铁载体-头孢菌素偶联体，并深入研究其构效、构代和构毒关系，本项目发现的YT-11S (III-10)体内外对多药耐药革兰氏阴性菌高度有效、代谢性质优良、毒性低、稳定性好，具有开发前景的候选化合物，为最终开发出拥有我国自主知识产权的创新药物奠定坚实的知识基础。申请专利1项，发表高水平SCI研究论文2篇，培养4名硕士和博士研究生。