八肽菌素衍生物的合成及其抗菌活性研究  

Synthesis and antibacterial activity evaluation of octapeptinderivatives

作　　者：杨鹤显 崔阿龙 王永健 寇世博 吕苗 易红[1] 李卓荣[1] YANG He-xian;CUI A-long;WANG Yong-jian;KOU Shi-bo;LÜMiao;YI Hong;LI Zhuo-rong(Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院、北京协和医学院医药生物技术研究所,北京100050

出　　处：《药学学报》2024年第1期152-160,共9页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金(82003600,32141003);中国医学科学院医学与健康科技创新工程(2021-I2M-1-030)。

摘　　要：八肽菌素在对大肠埃希菌、肺炎克雷伯菌、鲍曼不动杆菌等G-菌具有较强活性的同时,对部分G^(+)菌也有一定的活性。本研究以天然八肽菌素A3和B3为先导化合物进行结构改造,采用固相合成法制备了21个含有8个氨基酸残基的肽类衍生物(含A3和B3),并对其进行抗菌活性测试和肾细胞毒性评价。其中,化合物6、7和17显示有广谱抗菌活性,在维持抗G-菌活性的同时,明显提升了抗G^(+)菌活性;部分化合物提高了抗铜绿假单胞菌活性。化合物7对所有测定菌株均有活性且肾细胞毒性相对较低。本文研究结果为进一步发展新型多肽类抗菌药物奠定了一定的基础。Octapeptin has strong antibacterial activity against Gram-negative bacteria such as Escherichia coli,Klebsiella pneumoniae and Acinetobacter baumannii,while it also has activity against some Gram-positive bacteria.This study used natural octapeptin A3 and B3 as lead compounds for structural modification.Twenty-one peptide derivatives(including A3 and B3)containing eight amino acid residues were prepared by solid-phase synthesis,and evaluated for antibacterial activity and renal cytotoxicity.Among them,three compounds 6,7 and 17 exhibited broad-spectrum antibacterial activity and significantly enhanced the activity for Gram-positive bacteria while maintaining the activity of Gram-negative bacteria.Several compounds improved the activity for Pseudomonas aeruginosa.Compound 7 was active against all test strains and had relatively low renal cytotoxicity.The results provide a basis for the further development of novel polypeptide antibiotics.

关 键 词：细菌耐药 八肽菌素 结构修饰 广谱抗菌活性 

分 类 号：R914[医药卫生—药物化学]