Arginine-Containing Surfactant-Like Peptides: Interaction with Lipid Membranes and Antimicrobial Activity

Research output: Contribution to journalArticleScientificpeer-review

Researchers

  • Valeria Castelletto
  • Ruth H. Barnes
  • Kimon-Andreas Karatzas
  • Charlotte J. C. Edwards-Gayle
  • Francesca Greco
  • Ian W. Hamley
  • Robert Rambo
  • Jani Seitsonen

  • Janne Ruokolainen

Research units

  • University of Reading
  • Harwell Science and Innovation Campus

Abstract

The activity of antimicrobial peptides stems from their interaction with bacterial membranes, which are disrupted according to a number of proposed mechanisms. Here, we investigate the interaction of a model antimicrobial peptide that contains a single arginine residue with vesicles containing model lipid membranes. The surfactant-like peptide Ala(6)-Arg (A(6)R) is studied in the form where both termini are capped (CONH-A(6)R-NH2, capA(6)R) or uncapped (NH2-A(6)R-OH, A(6)R). Lipid membranes are selected to correspond to model anionic membranes (POPE/POPG) resembling those in bacteria or model zwitterionic membranes (POPC/DOPC) similar to those found in mammalian cells. Viable antimicrobial agents should show activity against anionic membranes but not zwitterionic membranes. We find, using small-angle X-ray scattering (SAXS) and cryogenic-TEM (transmission electron microscopy) that, uniquely, capA(6)R causes structuring of anionic membranes due to the incorporation of the peptide in the lipid bilayer with peptide beta-sheet conformation revealed by circular dichroism spectroscopy (CD). There is a preferential interaction of the peptide with POPG (which is the only anionic lipid in the systems studied) due to electrostatic interactions and bidentate hydrogen bonding between arginine guanidinium and lipid phosphate groups. At a certain composition, this peptide leads to the remarkable tubulation of zwitterionic phosphatidylcholine (PC) vesicles, which is ascribed to the interaction of the peptide with the outer lipid membrane, which occurs without penetration into the membrane. In contrast, peptide A(6)R has a minimal influence on the anionic lipid membranes (and no beta-sheet peptide structure is observed) but causes thinning (lamellar decorrelation) of zwitterionic membranes. We also investigated the cytotoxicity (to fibroblasts) and antimicrobial activity of these two peptides against model Gram positive and Gram negative bacteria. A strong selective antimicrobial activity against Gram positive Listeria monocytogenes, which is an important food-borne pathogen, is observed for capA(6)R. Peptide A(6)R is active against all three studied bacteria. The activity of the peptides against bacteria and mammalian cells is related to the specific interactions uncovered through our SAXS, cryo-TEM, and CD measurements. Our results highlight the exquisite sensitivity to the charge distribution in these designed peptides and its effect on the interaction with lipid membranes bearing different charges, and ultimately on antimicrobial activity.

Details

Original languageEnglish
Pages (from-to)2782-2794
Number of pages13
JournalBiomacromolecules
Volume19
Issue number7
Publication statusPublished - Jul 2018
MoE publication typeA1 Journal article-refereed

    Research areas

  • LISTERIA-MONOCYTOGENES LO28, ANTIBACTERIAL ACTIVITIES, SHAPE TRANSFORMATIONS, AMPHIPHILIC PEPTIDES, SECONDARY STRUCTURE, MECHANISMS, VESICLES, ACID, RESISTANCE, DESTABILIZATION

ID: 27449639