A short D-enantiomeric antimicrobial peptide with potent immunomodulatory and antibiofilm activity against multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii

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,...

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Bibliographic Details
Published in:	Scientific reports 2017-07, Vol.7 (1), p.6953-13, Article 6953
Main Authors:	Mohamed, Mohamed F, Brezden, Anna, Mohammad, Haroon, Chmielewski, Jean, Seleem, Mohamed N
Format:	Article
Language:	eng
Subjects:	Acinetobacter baumannii Acinetobacter baumannii - drug effects Animals Antibiotic resistance Antibiotics Antimicrobial activity Antimicrobial agents Antimicrobial Cationic Peptides - chemical synthesis Antimicrobial Cationic Peptides - chemistry Antimicrobial Cationic Peptides - pharmacology Antimicrobial peptides Biofilms Biofilms - drug effects Caenorhabditis elegans - microbiology Colistin Colistin - pharmacology Cystic fibrosis Cystic Fibrosis - microbiology Drug Design Drug resistance Drug Resistance, Multiple, Bacterial - drug effects Drug Stability Humans Immunomodulation Inflammation Lipopolysaccharides Macrophages Microbial Sensitivity Tests Pathogens Peptides pH effects Pseudomonas aeruginosa Pseudomonas aeruginosa - drug effects Pseudomonas Infections - microbiology Salts Strains (organisms)
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Summary:	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.
ISSN:	2045-2322 2045-2322