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Antimicrobial Agents and Chemotherapy, November 2002, p. 3585-3590, Vol. 46, No. 11
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.11.3585-3590.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Cationic Hydrophobic Peptides with Antimicrobial Activity

Margareta Stark, Li-Ping Liu,{dagger} and Charles M. Deber*

Division of Structural Biology and Biochemistry, Research Institute, Hospital for Sick Children, Toronto M5G 1X8, and Department of Biochemistry, University of Toronto, Toronto M5S 1A8, Ontario, Canada

Received 2 May 2002/ Returned for modification 14 June 2002/ Accepted 18 July 2002

The MICs of cationic, hydrophobic peptides of the prototypic sequence KKAAAXAAAAAXAAWAAXAAAKKKK-amide (where X is one of the 20 commonly occurring amino acids) are in a low micromolar range for a panel of gram-negative and gram-positive bacteria, with no or low hemolytic activity against human and rabbit erythrocytes. The peptides are active only when the average segmental hydrophobicity of the 19-residue core is above an experimentally determined threshold value (where X is Phe, Trp, Leu, Ile, Met, Val, Cys, or Ala). Antimicrobial activity could be increased by using peptides that were truncated from the prototype length to 11 core residues, with X being Phe and with 6 Lys residues grouped at the N terminus. We propose a mechanism for the interaction between these peptides and bacterial membranes similar to the "carpet model," wherein the Lys residues interact with the anionic phospholipid head groups in the bacterial membrane surface and the hydrophobic core portion of the peptide is then able to interact with the lipid bilayer, causing disruption of the bacterial membrane.

* Corresponding author. Mailing address: Division of Structural Biology and Biochemistry, Research Institute, Hospital for Sick Children, Toronto M5G 1X8, Canada. Phone: (416) 813-5924. Fax: (416) 813-5005. E-mail: deber{at}sickkids.ca.

{dagger} Present address: CTL ImmunoTherapies Corp., Chatsworth, CA 91311.

Antimicrobial Agents and Chemotherapy, November 2002, p. 3585-3590, Vol. 46, No. 11
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.11.3585-3590.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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