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Antimicrobial Agents and Chemotherapy, September 2009, p. 3705-3714, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00321-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Lipid Segregation Explains Selective Toxicity of a Series of Fragments Derived from the Human Cathelicidin LL-37{triangledown}

Raquel F. Epand,1 Guangshun Wang,2 Bob Berno,3 and Richard M. Epand1*

Department of Biochemistry and Biomedical Sciences,1 Department of Chemistry, McMaster University, Hamilton, Ontario L8N 3Z5, Canada,3 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-68052

Received 9 March 2009/ Returned for modification 9 June 2009/ Accepted 26 June 2009

The only human cathelicidin, the 37-residue peptide LL-37, exhibits antimicrobial activity against both gram-positive and gram-negative bacteria. We studied the ability of several fragments of LL-37, exhibiting different antimicrobial activities, to interact with membranes whose compositions mimic the cytoplasmic membranes of gram-positive or of gram-negative bacteria. These fragments are as follows: KR-12, the smallest active segment of LL-37, with the sequence KRIVQRIKDFLR, which exhibits antimicrobial activity only against gram-negative bacteria; a slightly smaller peptide, RI-10, missing the two cationic residues at the N and C termini of KR-12, which has been shown not to have any antimicrobial activity; a longer peptide, GF-17, which shows antimicrobial activity against gram-positive as well as gram-negative bacteria; and GF-17D3, with 3 D-amino-acid residues, which is also selective only for gram-negative bacteria. Those fragments with the capacity to cluster anionic lipids away from zwitterionic lipids in a membrane exhibit selective toxicity toward bacteria containing zwitterionic as well as anionic lipids in their cytoplasmic membranes but not toward bacteria with only anionic lipids. This finding allows for the prediction of the bacterial-species selectivity of certain agents and paves the way for designing new antimicrobials targeted specifically toward gram-negative bacteria.

* Corresponding author. Mailing address: Department of Biochemistry and Biomedical Sciences, McMaster University Health Sciences Centre, Hamilton, Ontario L8N 3Z5, Canada. Phone: (905) 525-9140. Fax: (905) 521-1397. E-mail: epand{at}mcmaster.ca

{triangledown} Published ahead of print on 6 July 2009.

Antimicrobial Agents and Chemotherapy, September 2009, p. 3705-3714, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00321-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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