Mohamed, Mohamed F.Brezden, AnnaMohammad, HaroonChmielewski, JeanSeleem, Mohamed N.2020-09-212020-09-212017-07-312045-232210.1038/s41598-017-07440-0 (PII)http://hdl.handle.net/10919/100014Antimicrobial 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.13 page(s)Electronicapplication/pdfenCreative Commons Attribution 4.0 InternationalINTRACELLULAR PATHOGENIC BACTERIACYSTIC-FIBROSIS PATIENTSHOST-DEFENSE PEPTIDESIN-VIVOANTIBACTERIAL ACTIVITYINFECTION MODELPLAUSIBLE MODEHUMAN SERUMIDENTIFICATIONMECHANISMAnimalsHumansCaenorhabditis elegansBiofilmsAcinetobacter baumanniiPseudomonas aeruginosaPseudomonas InfectionsCystic FibrosisColistinAntimicrobial Cationic PeptidesMicrobial Sensitivity TestsDrug StabilityDrug Resistance, Multiple, BacterialDrug DesignArticle - Refereed2020-09-21https://doi.org/10.1038/s41598-017-07440-071Seleem, Mohamed [0000-0003-0939-0458]28761101 (pubmed)2045-2322