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Antimicrobial Agents and Chemotherapy, April 2007, p. 1398-1406, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.00925-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Role of Peptide Hydrophobicity in the Mechanism of Action of -Helical Antimicrobial Peptides

Department of Biochemistry and Molecular Genetics,¹ Department of Microbiology, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 80045²

Received 26 July 2006/ Returned for modification 13 October 2006/ Accepted 1 December 2006

In the present study, the 26-residue amphipathic -helical antimicrobial peptide V13K_L (Y. Chen et al., J. Biol. Chem. 2005, 280:12316-12329, 2005) was used as the framework to study the effects of peptide hydrophobicity on the mechanism of action of antimicrobial peptides. Hydrophobicity was systematically decreased or increased by replacing leucine residues with less hydrophobic alanine residues or replacing alanine residues with more hydrophobic leucine residues on the nonpolar face of the helix, respectively. Hydrophobicity of the nonpolar face of the amphipathic helix was demonstrated to correlate with peptide helicity (measured by circular dichroism spectroscopy) and self-associating ability (measured by reversed-phase high-performance liquid chromatography temperature profiling) in aqueous environments. Higher hydrophobicity was correlated with stronger hemolytic activity. In contrast, there was an optimum hydrophobicity window in which high antimicrobial activity could be obtained. Decreased or increased hydrophobicity beyond this window dramatically decreased antimicrobial activity. The decreased antimicrobial activity at high peptide hydrophobicity can be explained by the strong peptide self-association which prevents the peptide from passing through the cell wall in prokaryotic cells, whereas increased peptide self-association had no effect on peptide access to eukaryotic membranes.

Published ahead of print on 11 December 2006.