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

Abstract

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, <1 % hemolysis of red blood cells was observed.

The Potential of Modified and Multimeric Antimicrobial Peptide Materials as Superbug Killers

“…The Arg/Trp-rich nature of these short peptides also contribute to their activity, making their activity as a function of length incomparable to the activity of the KIA peptide series ( Strøm et al, 2002 ). Ultrashort 3 residues long Arg/Trp-rich peptides are another inactive peptide, although when they are multimerised onto divalent and trivalent benzene scaffolds, the resulting compounds have higher activity that show negligible haemolysis, revealing multimerisation as another tool for improving AMPs ( Hoffknecht et al, 2015 ).…”

Julius von Haast Fellowship Award: N. Metzler‐Nolte / Preis der Chica und Heinz Schaller‐Stiftung: E. A. Lemke / Innovationspreis NRW: R. Schlögl / Goldmedaille der Università degli Studi di Firenze: J. M. Thomas

“…Sein Forschungsinteresse gilt der Bioorganometallchemie, wobei der Schwerpunkt Anwendungen von Metall‐Peptid‐Biokonjugaten und der medizinischen Organometallchemie in der Biomedizin für Diagnose und Therapie und in der Bioanalytik sind. In ChemMedChem hat er antimikrobielle Peptide vorgestellt und in ChemBioChem Peptidbiokonjugate von elektronenarmen Metallocenen . Metzler‐Nolte gehörte 2007–2013 dem International Advisory Board des European Journal of Inorganic Chemistry an.…”

Julius von Haast Fellowship Award: N. Metzler‐Nolte / Chica and Heinz Schaller Research Award: E. A. Lemke / NRW Innovation Prize: R. Schlögl / Gold Medal, Università degli Studi di Firenze: J. M. Thomas

“…Metzler‐Nolte and his group are interested in bioorganometallic chemistry, with an emphasis on metal–peptide bioconjugates and medicinal organometallic chemistry, with applications in biomedicine as diagnostic and therapeutic agents, and in bioanalytics. He has reported in ChemMedChem on antimicrobial peptides, and in ChemBioChem on peptide bioconjugates of electron‐poor metallocenes . Metzler‐Nolte was on the International Advisory Board of the European Journal of Inorganic Chemistry from 2007–2013.…”