Short Antimicrobial Peptides Based on Arginine and Tryptophan: Agents with Potential in Combating Resistant Pathogens

TL;DR

This study explores short peptides made of arginine and tryptophan that show strong antimicrobial activity and could help combat drug-resistant bacteria.

Contribution

The design and evaluation of short Arg/Trp-based peptides with potent antimicrobial activity and synergy with existing antibiotics.

Findings

(WRW)2F showed the strongest bactericidal activity against tested pathogens, including resistant strains.

The peptides caused rapid membrane disruption and did not inhibit efflux pumps.

Three peptides synergized with linezolid and (WRW)2F resensitized MRSA to oxacillin.

Abstract

The limitations of
conventional antibiotics due to the
rise of
antimicrobial resistance demand new therapeutic strategies. Antimicrobial
peptides represent a promising alternative because of their broad-spectrum
activity and low propensity for inducing resistance. In this study,
we designed and evaluated a set of seven-residue Arg/Trp-based peptides.
All peptides were successfully synthesized and characterized, and
their activities were assessed against Escherichia
coli, Pseudomonas aeruginosa, and Staphylococcus aureus, including
clinical isolates. Among the sequences tested, (WRW)2F
exhibited the strongest antimicrobial activity, displaying bactericidal
effects. Growth inhibition and time-kill assays showed dose-dependent
effects, and SYTOX Green uptake, AFM, and TEM analyses confirmed rapid
membrane permeabilisation and structural disruption as the primary
mode of action, while it has been demonstrated not to act as an efflux
pump inhibitors. Importantly, the three more active peptides synergized
with linezolid against E. coli, and
(WRW)2F was able to resensitize MRSA to oxacillin, demonstrating
their potential for combined therapies. The toxicity studies in eukaryotic
cells and the C. elegans survival model
have shown a favorable safety profile. Overall, this work highlights
short Arg/Trp-rich peptides, especially (WRW)2F, as affordable,
easy-to-synthesize, and biocompatible compounds with significant potential
to enhance antibiotic efficacy and counteract resistant pathogens.

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