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Antimicrobial Agents and Chemotherapy, December 2005, p. 4957-4964, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.4957-4964.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Antimicrobial Activities and Structures of Two Linear Cationic Peptide Families with Various Amphipathic ß-Sheet and {alpha}-Helical Potentials

Yi Jin,2 Janet Hammer,1 Michelle Pate,1 Yu Zhang,2,3 Fang Zhu,2,3 Erik Zmuda,1 and Jack Blazyk1,2,3*

Department of Biomedical Sciences, College of Osteopathic Medicine,1 Department of Chemistry and Biochemistry,2 Molecular and Cellular Biology Program, College of Arts & Sciences, Ohio University, Athens, Ohio 457013

Received 2 June 2005/ Returned for modification 9 August 2005/ Accepted 9 September 2005

Many naturally occurring antimicrobial peptides comprise cationic linear sequences with the potential to adopt an amphipathic {alpha}-helical conformation. We designed a linear 18-residue peptide that adopted an amphipathic ß-sheet structure when it was bound to lipids. In comparison to a 21-residue amphipathic {alpha}-helical peptide of equal charge and hydrophobicity, this peptide possessed more similar antimicrobial activity and greater selectivity in binding to and inducing leakage in vesicles composed of bacterial membrane lipids than vesicles composed of mammalian membrane lipids (J. Blazyk, R. Weigand, J. Klein, J. Hammer, R. M. Epand, R. F. Epand, W. L. Maloy, and U. P. Kari, J. Biol. Chem. 276:27899-27906, 2001). Here, we compare two systematically designed families of linear cationic peptides to evaluate the importance of amphipathicity for determination of antimicrobial activity. Each peptide contains six lysine residues and is amidated at the carboxyl terminus. The first family consists of five peptides with various capacities to form amphipathic ß-sheet structures. The second family consists of six peptides with various potentials to form amphipathic {alpha} helices. Only those peptides that can form a highly amphipathic structure (either a ß sheet or an {alpha} helix) possessed significant antimicrobial activities. Striking differences in the abilities to bind to and induce leakage in membranes and lipid vesicles were observed for the two families. Overall, the amphipathic ß-sheet peptides are less lytic than their amphipathic {alpha}-helical counterparts, particularly toward membranes containing phosphatidylcholine, a lipid commonly found in mammalian plasma membranes. Thus, it appears that antimicrobial peptides that can form an amphipathic ß-sheet conformation may offer a selective advantage in targeting bacterial cells.

* Corresponding author. Mailing address: Department of Biomedical Sciences, 234 Grosvenor Hall, Ohio University College of Osteopathic Medicine, Athens, OH 45701. Phone: (740) 593-1742. Fax: (740) 593-2320. E-mail: blazyk{at}ohiou.edu.

Antimicrobial Agents and Chemotherapy, December 2005, p. 4957-4964, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.4957-4964.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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