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Antimicrobial Agents and Chemotherapy, August 2006, p. 2666-2672, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.00030-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Physicochemical Properties That Enhance Discriminative Antibacterial Activity of Short Dermaseptin Derivatives

Shahar Rotem, Inna Radzishevsky, and Amram Mor^*

Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, 32000 Haifa, Israel

Received 9 January 2006/ Returned for modification 8 March 2006/ Accepted 12 May 2006

Antimicrobial peptides are widely believed to exert their effects by nonspecific mechanisms. We assessed the extent to which physicochemical properties can be exploited to promote discriminative activity by manipulating the N-terminal sequence of the 13-mer dermaseptin derivative K₄-S4(1-13) (P). Inhibitory activity determined in culture media against 16 strains of bacteria showed that when its hydrophobicity and charge were changed, P became predominantly active against either gram-positive or gram-negative bacteria. Thus, conjugation of various aminoacyl-lysin moieties (e.g., aminohexyl-K-P) led to inactivity against gram-positive bacteria (MIC₅₀ > 50 µM) but potent activity against gram-negative bacteria (MIC₅₀, 6.2 µM). Conversely, conjugation of equivalent acyls to the substituted analog M₄-S4(1-13) (e.g., hexyl-M₄-P) led to inactivity against gram-negative bacteria (MIC₅₀ > 50 µM) but potent activity against gram-positive bacteria (MIC₅₀, 3.1 µM). Surface plasmon resonance experiments, used to investigate peptides' binding properties to lipopolysaccharide-containing idealized phospholipid membranes, suggest that although the acylated derivatives have increased lipophilic properties with parallel antibacterial behavior, hydrophobic derivatives are prevented from reaching the cytoplasmic membranes of gram-negative bacteria. Moreover, unlike modifications that enhanced the activity against gram-positive bacteria, which also enhanced hemolysis, we found that modifications that enhanced activity against gram-negative bacteria generally reduced hemolysis. Thus, compared with the clinically tested peptides MSI-78 and IB-367, the dermaseptin derivative aminohexyl-K-P performed similarly in terms of potency and bactericidal kinetics but was significantly more selective in terms of discrimination between bacteria and human erythrocytes. Overall, the data suggest that similar strategies maybe useful to derive potent and safe compounds from known antimicrobial peptides.

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* Corresponding author. Mailing address: Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, 32000 Haifa, Israel. Phone: (972) 4-829-3340. Fax: (972) 4-829-3399. E-mail: amor{at}tx.technion.ac.il.

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Antimicrobial Agents and Chemotherapy, August 2006, p. 2666-2672, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.00030-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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