Design, synthesis, and biological evaluation of novel polymyxin B analogues
10.16438/j.0513-4870.2019-0500
- VernacularTitle:新型多黏菌素B衍生物的设计合成及生物功能研究
- Author:
A-long CUI
1
;
Xin-xin HU
1
;
Yan GAO
1
;
Jie JIN
1
;
Hong YI
1
;
Yang CHEN
1
;
Qi-yang HE
1
;
Xue-fu YOU
1
;
Zhuo-rong LI
1
Author Information
1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- Publication Type:Research Article
- Keywords:
gram-negative pathogens;
polymyxin B;
novel analogues;
antimicrobial activity;
nephrotoxicity
- From:
Acta Pharmaceutica Sinica
2019;54(11):2031-2038
- CountryChina
- Language:Chinese
-
Abstract:
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 position 6 amino acid. 20 polymyxin B analogues were synthesized and the chemical structures of the analogues were confirmed by HR-MS and 1H NMR spectra. Compounds 7e (MIC: 0.5-4 μg·mL-1) and 7l (MIC: 0.25-2 μg·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: 0.5-2 μg·mL-1). Besides, compound 7l (CC50: 217.1±13.2 μg·mL-1) displayed noticeably decreased renal cytotoxicity compared to polymyxin B (CC50: 120.3±6.0 μg·mL-1). This work establishes the base of further study on the structure-activity relationship of polymyxin B.
