Effect of Electrostatic Interactions on the Membrane Interactions of Amphiphilic Peptides with Antimicrobial Potential

Abstract

A wide variety of organisms produce antimicrobial peptides as part of their first line of defense. These short cationic peptides are being considered as a new generation of antibiotics and represent great hopes against multiresistant bacteria which are an important clinical problem. Despite their diversity, antimicrobial peptides generally share common characteristics such as a short length of amino acids, a positive charge and an amphiphilic character. Also, it is important to note that the main target of antimicrobial peptides is the membrane(s) of pathogens. We have previously shown that a non-natural peptide composed of 14 residues (10 leucines and 4 phenylalanines modified with a crown ether) has a helical secondary structure, and is able to disrupt lipid bilayers but is not selective towards bacterial membranes. To gain specificity against negatively charged membranes, several leucines of this 14-mer have been substituted by positively charged residues (lysine, arginine, histidine). In addition, we have compared the results with those obtained with peptides substituted with negatively charged residues. Solid-state NMR experiments performed in model membranes and lipids oriented between glass plates were used to better characterize the mode of action of the charged peptides. In addition, It has been possible to determine the orientation of the charged peptides relative to the bilayer normal by using attenuated total reflection spectroscopy. Complementary results have also been obtained by infrared and fluorescence spectroscopy. The results indicate significant differences in the membrane interactions of cationic and anionic peptides, confirming the importance of electrostatic interactions.