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J. Biol. Chem., Vol. 280, Issue 40, 33960-33967, October 7, 2005

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Basis for Selectivity of Cationic Antimicrobial Peptides for Bacterial Versus Mammalian Membranes^*

Evgenia Glukhov¶1, Margareta Stark¶2, Lori L. Burrows||, and Charles M. Deber¶3

From the Divisions of Structural Biology and Biochemistry, and Infection, Immunity, Injury and Repair, Research Institute, Hospital for Sick Children, Toronto, Ontario M5S 1A8, and the Departments of ^¶Biochemistry and ^||Surgery, University of Toronto, Toronto, Ontario M5G 1X8 Canada

Novel cationic antimicrobial peptides typified by structures such as KKKKKKAAXAAWAAXAA-NH₂, where X = Phe/Trp, and several of their analogues display high activity against a variety of bacteria but exhibit no hemolytic activity even at high dose levels in mammalian erythrocytes. To elucidate their mechanism of action and source of selectivity for bacterial membranes, phospholipid mixtures mimicking the compositions of natural bacterial membranes (containing anionic lipids) and mammalian membranes (containing zwitterionic lipids + cholesterol) were challenged with the peptides. We found that peptides readily inserted into bacterial lipid mixtures, although no insertion was detected in model "mammalian" membranes. The depth of peptide insertion into model bacterial membranes was estimated by Trp fluorescence quenching using doxyl groups variably positioned along the phospholipid acyl chains. Peptide antimicrobial activity generally increased with increasing depth of peptide insertion. The overall results, in conjunction with molecular modeling, support an initial electrostatic interaction step in which bacterial membranes attract and bind peptide dimers onto the bacterial surface, followed by the "sinking" of the hydrophobic core segment to a peptide sequence-dependent depth of 2.5–8 Å into the membrane, largely parallel to the membrane surface. Antimicrobial activity was likely enhanced by the fact that the peptide sequences contain AXXXA sequence motifs, which promote their dimerization, and possibly higher oligomerization, as assessed by SDS-polyacrylamide gel analysis and fluorescence resonance energy transfer experiments. The high selectivity of these peptides for nonmammalian membranes, combined with their activity toward a wide spectrum of Gram-negative and Gram-positive bacteria and yeast, while retaining water solubility, represent significant advantages of this class of peptides.

Received for publication, June 28, 2005 , and in revised form, July 21, 2005.

^* This work was supported in part by grants from the Canadian Infectious Diseases Society (to L. L. B.), the Canadian Institutes of Health Research (to C. M. D.), and the Natural and Engineering Research Council of Canada (to C. M. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a postdoctoral award from the Canadian Institutes of Health Research Strategic Training Program in Structural Biology of Membrane Proteins Linked to Disease.

² Recipient of a Sweden-America Foundation award in 2001-2002. Present address: Dept. of Molecular Biosciences, Swedish University of Agricultural Sciences, Biomedical Centre, Box 575, S-75123 Uppsala, Sweden.

³ To whom correspondence should be addressed. Fax: 416-813-5005; E-mail: deber{at}sickkids.ca.

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