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.

译文

抗菌肽 (AMPs) 是治疗抗生素耐药性细菌感染的一种有前途的治疗选择。本研究调查了短 α-螺旋肽RR的新的,合理设计的衍生物的抗菌活性。从设计的肽中,RR4及其D-对映异构体D-RR4成为最有效的类似物,对铜绿假单胞菌和鲍曼不动杆菌的多重耐药菌株的抗菌活性提高了32倍以上。值得注意的是,D-RR4显示出对铜绿假单胞菌 (从囊性纤维化患者中分离出) 的粘菌素抗性菌株的有效活性,表明该肽在几种AMPs上具有潜在的治疗优势。与许多天然amp相比,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,与常规抗生素相比,D-RR4更有能力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能够与脂多糖结合以减少巨噬细胞中内毒素诱导的促炎性细胞因子反应。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,并增强粘菌素在体内抵抗粘菌素抗性铜绿假单胞菌的活性。

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