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

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.

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