Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, 47907, USA.
Department of Chemistry, Purdue University, West Lafayette, IN, 47907, USA.
Sci Rep. 2017 Jul 31;7(1):6953. doi: 10.1038/s41598-017-07440-0.
Antimicrobial peptides (AMPs) represent a promising therapeutic alternative for the treatment of antibiotic-resistant bacterial infections. The present study investigates the antimicrobial activity of new, rationally-designed derivatives of a short α-helical peptide, RR. From the peptides designed, RR4 and its D-enantiomer, D-RR4, emerged as the most potent analogues with a more than 32-fold improvement in antimicrobial activity observed against multidrug-resistant strains of Pseudomonas aeruginosa and Acinetobacter baumannii. Remarkably, D-RR4 demonstrated potent activity against colistin-resistant strains of P. aeruginosa (isolated from cystic fibrosis patients) indicating a potential therapeutic advantage of this peptide over several AMPs. In contrast to many natural AMPs, D-RR4 retained its activity under challenging physiological conditions (high salts, serum, and acidic pH). Furthermore, D-RR4 was more capable of disrupting P. aeruginosa and A. baumannii biofilms when compared to conventional antibiotics. Of note, D-RR4 was able to bind to lipopolysaccharide to reduce the endotoxin-induced proinflammatory cytokine response in macrophages. Finally, D-RR4 protected Caenorhabditis elegans from lethal infections of P. aeruginosa and A. baumannii and enhanced the activity of colistin in vivo against colistin-resistant P. aeruginosa.
抗菌肽 (AMPs) 是一种很有前途的治疗方法，可以替代抗生素来治疗对抗生素有耐药性的细菌感染。本研究调查了一种短 α-螺旋肽 RR 的新设计的、合理设计的衍生物的抗菌活性。在所设计的肽中，RR4 及其 D-对映体 D-RR4 是最有效的类似物，对多药耐药的铜绿假单胞菌和鲍曼不动杆菌的抗菌活性提高了 32 倍以上。值得注意的是，D-RR4 对耐粘菌素的铜绿假单胞菌（从囊性纤维化患者中分离出来）表现出强大的活性，表明与几种 AMP 相比，这种肽具有潜在的治疗优势。与许多天然 AMP 不同，D-RR4 在具有挑战性的生理条件（高盐、血清和酸性 pH）下保持其活性。此外，与传统抗生素相比，D-RR4 更能破坏铜绿假单胞菌和鲍曼不动杆菌生物膜。值得注意的是，D-RR4 能够与脂多糖结合，从而减少巨噬细胞中内毒素诱导的促炎细胞因子反应。最后，D-RR4 保护秀丽隐杆线虫免受铜绿假单胞菌和鲍曼不动杆菌的致命感染，并增强了体内对耐粘菌素的铜绿假单胞菌的粘菌素活性。
