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

• Published in: FEBS letters Vol. 501; no. 2; pp. 146 - 150
• Main Authors: Dathe, Margitta, Nikolenko, Heike, Meyer, Jana, Beyermann, Michael, Bienert, Michael
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 20-07-2001
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial peptide; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacology; Binding Sites; CD, circular dichroism; EDTA, ethylenediaminetetraacetic acid; Escherichia coli - drug effects; Fmoc, 9-fluorenylmethoxy-carbonyl; H hd, hydrophobicity of the hydrophobic helix surface; H, hydrophobicity; Hemolysis; Hemolysis - drug effects; HPLC, high performance liquid chromatography; Humans; LUVs, large unilamellar vesicles; Magainin; Magainins; MIC, minimum inhibitory concentration; Microbial Sensitivity Tests; MIIa, magainin II amide; OD, optical density; Peptide charge; Peptides - chemistry; Peptides - pharmacology; Permeability - drug effects; POPC, 1-palmitoyl-2-oleoylphosphatidylcholine; POPG, 1-palmitoyl-2-oleoylphosphatidyl-DL-glycerol; Protein Conformation; SUVs, small unilamellar vesicles; TFE, 2,2,2-trifluoroethanol; Tris, tris(hydroxymethyl)aminomethane; Xenopus Proteins; Hemolysis; POPC, 1-palmitoyl-2-oleoylphosphatidylcholine; MIC, minimum inhibitory concentration; EDTA, ethylenediaminetetraacetic acid; H, hydrophobicity; LUVs, large unilamellar vesicles; OD, optical density; Peptide charge; H hd, hydrophobicity of the hydrophobic helix surface; SUVs, small unilamellar vesicles; HPLC, high performance liquid chromatography; TFE, 2,2,2-trifluoroethanol; Antibacterial peptide; MIIa, magainin II amide; POPG, 1-palmitoyl-2-oleoylphosphatidyl- DL-glycerol; Fmoc, 9-fluorenylmethoxy-carbonyl; Magainin; Tris, tris(hydroxymethyl)aminomethane; CD, circular dichroism
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/S0014-5793(01)02648-5

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.