Optimization of the antimicrobial activity of magainin peptides by modification of charge

TLDR

Dye‑release assays on negatively charged lipid vesicles showed that increasing peptide charge can reduce membrane activity, limiting the role of electrostatics. Increasing magainin II charge to +5 improves antimicrobial activity and selectivity, but higher charges raise hemolysis; selectivity can be recovered by lowering the hydrophobic surface (H hd), which also compensates for charge‑induced activity loss on negatively charged membranes.

Abstract

Investigation of magainin II amide analogs with cationic charges ranging between +3 and +7 showed that enhancement of the peptide charge up to a threshold value of +5 and conservation of appropriate hydrophobic properties optimized the antimicrobial activity and selectivity. High selectivity was the result of both enhanced antimicrobial and reduced hemolytic activity. Charge increase beyond +5 with retention of other structural motifs led to a dramatic increase of hemolytic activity and loss of antimicrobial selectivity. Selectivity could be restored by reduction of the hydrophobicity of the hydrophobic helix surface ( H hd ), a structural parameter not previously considered to modulate activity. Dye release experiments with lipid vesicles revealed that the potential of peptide charge to modulate membrane activity is limited: on highly negatively charged 1‐palmitoyl‐2‐oleoylphosphatidyl‐ DL ‐glycerol bilayers, reinforcement of electrostatic interactions had an activity‐reducing effect. On neutral 1‐palmitoyl‐2‐oleoylphosphatidylcholine bilayers, the high activity was determined by H hd . H hd values above a certain threshold led to effective permeabilization of all lipid systems and even compensated for the activity‐reducing effect of charge increase on highly negatively charged membranes.