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

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. ß

Physical Basis for Membrane-Charge Selectivity of Cationic Antimicrobial Peptides

“…This naturally arises from the fact that peptide's binding affinity for a highly charged surface can be maximized at a certain value of Q, but it decreases monotonically with Q for a neutral surface. Also, our results not only show how Q and peptide's hydrophobicity are intertwined in determining the hydrophobic insertion but also are consistent with high-Q requirements for antimicrobial selectivity [8][9][10]. They indicate that, to optimize the selectivity, larger Q is needed for higher hydrophobicity.…”

“…For " I ÿ12k B T, which typifies magainin II, Q 5-6 (see the dotted line). In an experimental study [8], the charge of magainin II analogs was modulated between 3 and 7 with other parameters conserved. Antimicrobial selectivity was then studied by dye release (see Ref.…”

“…Peptides are modeled as a thin circular disk carrying a charge Q; molecular details such as their hydrophobicity will be subsumed into a few parameters. Recent work on magainin II analogs indicates that Q and peptide's hydrophobicity can be modified almost independently [8]. Similarly we consider them as independent parameters.…”

Computational Design of Highly Selective Antimicrobial Peptides

“…Lower and higher net positive charge decreases both peptide activity and selectivity for peptides with about 20 amino acids. 9 At the x-axis of the Figure 4, higher predicted TI is associated with increased net positive charge of the peptides. The E14K substitution is an exception, since it increased pseudin charge from +2 to +4 but did not increase predicted and measured TI.…”

Scorpion venom as antimicrobial peptides (AMPs): A review article

“…Charge: Positive charge of cationic AMPs play an important role in the initial electrostatic attachment to the targeted negatively charged membranes components like acidic phospholipids, LPS and teichoic or teichuronic acid of gram negative and gram positive bacteria [15]. Many of AMPs are reported to have a net positive charge ranging from +2 to +9, there is a direct relationship between peptides net positive charge and activity within limited range differ in different peptides, increase the charge up the limit or decrease it below the limit resulted in the loss of optimum activity [24].…”