新型多黏菌素B衍生物的设计合成及生物功能研究  

Design, synthesis, and biological evaluation of novel polymyxin B analogues

作　　者：崔阿龙 胡辛欣[1] 高岩[1] 金洁[1] 易红[1] 陈阳[1] 何琪杨[1] 游雪甫[1] 李卓荣[1] CUI A-long;HU Xin-xin;GAO Yan;JIN Jie;YI Hong;CHEN Yang;HE Qi-yang;YOU Xue-fu;LI Zhuo-rong(Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and 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

出　　处：《药学学报》2019年第11期2031-2038,共8页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金面上项目(81773585);中国医学科学院医学与健康科技创新工程(2017-I2M-1-012)

摘　　要：多黏菌素B和多黏菌素E(黏菌素)成为治疗多药耐药革兰氏阴性菌的"最后一道防线",但是多黏菌素存在严重的肾毒性,限制了其临床使用。因此,急需研发新型高效、低毒的多黏菌素衍生物。本研究通过改变N-取代脂肪酰基链或6位D-Phe的疏水性和体积设计合成两类多黏菌素B衍生物20个,并评价其生物活性。衍生物结构经高分辨质谱(HR-MS)和核磁共振氢谱(1H NMR)确证,与多黏菌素B(MIC:0.5~2μg·mL^-1,CC50:120.3±6.0μg·mL^-1)相比,衍生物7e(MIC:0.5~4μg·mL^-1)和7l(MIC:0.25~2μg·mL^-1)对测定的耐药或敏感的大肠埃希菌、肺炎克雷伯菌、鲍曼不动杆菌和铜绿假单胞菌显示出相当或提高的抗菌活性,同时衍生物7l(CC50:217.1±13.2μg·mL^-1)的肾细胞毒性降低。本研究为多黏菌素B的构效关系研究奠定基础。Polymyxin B and polymyxin E(colistin)are increasingly used as last-resort drugs for treatment of infections caused by multidrug-resistant gram-negative pathogens.Unfortunately,the application was limited due to the serious side effects,especially nephrotoxicity.Very recently,the need for developing more tolerated and more effective polymyxin analogues has grown.This study details the design,synthesis,and evaluation of two classes of polymyxin B analogues with varying hydrophobicity and bulkiness at the N-terminal fatty acyl chain or position6 amino acid.20 polymyxin B analogues were synthesized and the chemical structures of the analogues were confirmed by HR-MS and1 H NMR spectra.Compounds 7 e(MIC:0.5-4μg·mL^-1)and 7 l(MIC:0.25-2μg·mL^-1)showed similar or better antimicrobial activity against both susceptible and resistant strains of Escherichia coli,Klebsiella pneumoniae,Acinetobacter baumannii,and Pseudomonas aeruginosa compared to polymyxin B(MIC:0.5-2μg·mL^-1).Besides,compound 7 l(CC50:217.1±13.2μg·mL^-1)displayed noticeably decreased renal cytotoxicity compared to polymyxin B(CC50:120.3±6.0μg·mL^-1).This work establishes the base of further study on the structure-activity relationship of polymyxin B.

关 键 词：革兰氏阴性菌 多黏菌素B 新衍生物 抗菌活性 肾毒性 

分 类 号：R916[医药卫生—药学]