Design, synthesis, and biological evaluation of novel polymyxin B analogues / 药学学报

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.