Effects of net charge and the number of positively charged residues on the biological activity of amphipathic α‐helical cationic antimicrobial peptides

Abstract

In our previous study, we utilized a 26‐residue amphipathic α‐helical antimicrobial peptide L‐V13K (Chen et al., Antimicrob Agents Chemother 2007, 51, 1398–1406) as the framework to study the effects of peptide hydrophobicity on the mechanism of its antimicrobial action. In this study, we explored the effects of net charge and the number of positively charged residues on the hydrophilic/polar face of L‐V13K on its biological activity (antimicrobial and hemolytic) and biophysical properties (hydrophobicity, amphipathicity, helicity, and peptide self‐association). The net charge of V13K analogs at pH 7 varied between −5 and +10 and the number of positively charged residues varied from 1 to 10. The minimal inhibitory concentrations (MIC) against six strains of Pseudomonas aeruginosa as well as other gram‐negative and gram‐positive bacteria were determined along with the maximal peptide concentration that produces no hemolysis of human red blood cells (MHC). Our results show that the number of positively charged residues on the polar face and net charge are both important for both antimicrobial activity and hemolytic activity. The most dramatic observation is the sharp transition of hemolytic activity on increasing one positive charge on the polar face of V13K i.e., the change from +8 to +9 resulted in greater than 32‐fold increase in hemolytic activity (250 μg/ml to <7.8 μg/ml, respectively). © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 369–383, 2008.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

Opposing effects of cationic antimicrobial peptides and divalent cations on bacterial lipopolysaccharides

“…It is worth noting that Q can be varied while other peptide parameter are held fixed [27,[52][53][54]. This justifies our consideration of peptide-parameter-activity relationships.…”

Cationic Amphiphiles, a New Generation of Antimicrobials Inspired by the Natural Antimicrobial Peptide Scaffold

“…The increased charge raises electrostatic interactions between AMPs and the negatively charged bacterial membranes, without affecting interactions with the zwitterionic lipids found in mammalian membranes (44,81). Systematically increasing the positive charge of V 681 -V13K revealed a threshold, past which hemolytic activity dramatically increases, with no significant change in activity against bacteria, as shown with V 681 -V13K/T15K/T19K in Table 2 (34). As many oligocationic molecules are cell penetrating, it may be that highly charged AMPs, drawn by the negative membrane potential inside the cell, are inserting into mammalian cells (67).…”

Antibacterial and anticancer activity of a series of novel peptides incorporating cyclic tetra-substituted Cα amino acids

“…60 Jiang and co-workers also observed similar trends. 65 Varying the distance (estimated distances are given in Table 4) between the polypeptide backbone and the positively charged side chain amine group defines three physicochemical properties 1) side chain molecular flexibility, defines the total 3D conformational space available to the AMP on binding to the surface of the bacterial membrane . 44 2) delocalization of the positive charge density of the side chain amine functionality, (We have shown using electrostatic surface potential maps the shorter the side chain, the closer the positive charge of the amine nitrogen comes to the partially negatively charged carbonyl oxygens of the peptide backbone.…”