Design, antimicrobial activity and mechanism of action of Arg-rich ultra-short cationic lipopeptides

PLoS One. 2019 Feb 21;14(2):e0212447. doi: 10.1371/journal.pone.0212447. eCollection 2019.

Abstract

The increasing emergence of multidrug-resistant microorganisms represents one of the greatest challenges in the clinical management of infectious diseases, and requires the development of novel antimicrobial agents. To this aim, we de novo designed a library of Arg-rich ultra-short cationic antimicrobial lipopeptides (USCLs), based on the Arg-X-Trp-Arg-NH2 peptide moiety conjugated with a fatty acid, and investigated their antibacterial potential. USCLs exhibited an excellent antimicrobial activity against clinically pathogenic microorganisms, in particular Gram-positive bacteria, including multidrug resistant strains, with MIC values ranging between 1.56 and 6.25 μg/mL. The capability of the two most active molecules, Lau-RIWR-NH2 and Lau-RRIWRR-NH2, to interact with the bacterial membranes has been predicted by molecular dynamics and verified on liposomes by surface plasmon resonance. Both compounds inhibited the growth of S. aureus even at sub MIC concentrations and induced cell membranes permeabilization by producing visible cell surface alterations leading to a significant decrease in bacterial viability. Interestingly, no cytotoxic effects were evidenced for these lipopeptides up to 50-100 μg/mL in hemolysis assay, in human epidermal model and HaCaT cells, thus highlighting a good cell selectivity. These results, together with the simple composition of USCLs, make them promising lead compounds as new antimicrobials.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Infective Agents / chemistry*
  • Anti-Infective Agents / pharmacology*
  • Anti-Infective Agents / toxicity
  • Antimicrobial Cationic Peptides / chemistry*
  • Antimicrobial Cationic Peptides / pharmacology*
  • Antimicrobial Cationic Peptides / toxicity
  • Arginine / chemistry
  • Drug Design*
  • Drug Resistance, Microbial
  • Drug Resistance, Multiple
  • Gram-Positive Bacteria / drug effects
  • Hemolysis / drug effects
  • Humans
  • In Vitro Techniques
  • Microbial Sensitivity Tests
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Peptide Library
  • Staphylococcus aureus / drug effects
  • Staphylococcus aureus / ultrastructure

Substances

  • Anti-Infective Agents
  • Antimicrobial Cationic Peptides
  • Oligopeptides
  • Peptide Library
  • Arginine

Grants and funding

This study was carried out with the financial support of the University of Trieste (FRA 2016). F. Armas was supported by the fellowship grant ‘‘Made in Trieste’’ from the Area Science Park of Trieste. I declare that the commercial affiliation Arta Peptidion only provided support in the form of research materials, in particular this company provided us the lipopeptides used in this study. The company did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the “author contributions” section.