Influence of the Multivalency of Ultrashort Arg-Trp-Based Antimicrobial Peptides (AMP) on Their Antibacterial Activity

• Published in: ChemMedChem 2015-09, Vol.10 (9), p.1564-1569
• Main Authors: Hoffknecht, Barbara C., Worm, Dennis J., Bobersky, Sandra, Prochnow, Pascal, Bandow, Julia E., Metzler-Nolte, Nils
• Format: Article
• Language: English
• Subjects: Acinetobacter baumannii; Acinetobacter baumannii - drug effects; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; antibiotics; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacology; antimicrobial peptides; Arginine - chemistry; Click Chemistry; Drug Evaluation, Preclinical - methods; Hemolysis - drug effects; Humans; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; multivalency; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; solid-phase synthesis; Solid-Phase Synthesis Techniques; Staphylococcus aureus; Structure-Activity Relationship; Tryptophan - chemistry
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201500220

Peptide dendrimers are a class of molecules of high interest in the search for new antibiotics. We used microwave‐assisted, copper(I)‐catalyzed alkyne–azide cycloaddition (CuAAC; “click” chemistry) for the simple and versatile synthesis of a new class of multivalent antimicrobial peptides (AMPs) containing solely arginine and tryptophan residues. To investigate the influence of multivalency on antibacterial activity, short solid‐phase‐ synthesized azide‐modified Arg‐Trp‐containing peptides were “clicked” to three different alkyne‐modified benzene scaffolds to access scaffolds with one, two, or three peptides. The antibacterial activity of 15 new AMPs was investigated by minimal inhibitory concentration (MIC) assays on five different bacterial strains, including a multidrug‐resistant Staphylococcus aureus (MRSA) strain. With ultrashort (2–3 residues) peptides, a clear synergistic effect of the trivalent display was observed, whereas this effect was not apparent with longer peptides. The best candidates showed activities in the low‐micromolar range against Gram‐positive MRSA. Surprisingly, the best activity against Gram‐negative Acinetobacter baumannii was observed with an ultrashort dipeptide on the trivalent scaffold (MIC: 7.5 μM). The hemolytic activity was explored for the three most active peptides. At concentrations ten times the MIC values,