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Antimicrobial Agents and Chemotherapy, December 2006, p. 4153-4160, Vol. 50, No. 12
0066-4804/06/$08.00+0     doi:10.1128/AAC.00750-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Acyl-Substituted Dermaseptin S4 Derivatives with Improved Bactericidal Properties, Including on Oral Microflora{triangledown}

Y. Porat,1 K. Marynka,1 A. Tam,2 D. Steinberg,2 and A. Mor1*

Department of Biotechnology & Food Engineering, Laboratory of Antimicrobial Peptides Investigation (LAPI), Technion—Israel Institute of Technology, Haifa, Israel,1 Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University—Hadassah, Jerusalem, Israel2

Received 21 June 2006/ Returned for modification 1 August 2006/ Accepted 4 October 2006

The 15-mer dermaseptin S4 derivative S4(1-15) was recently shown to exhibit potent activity against oral pathogens associated with caries and periodontitis. Here, we investigated possible modes for improving the peptide's properties through systematic replacement of an N-terminal amino acid(s) with various fatty acids that modulate the peptide's hydrophobicity and/or charge. Deletion of 1 to 3 residues led to progressive loss of potency as assessed by MIC experiments performed on four test bacteria. Replacing the deleted amino acids with fatty acids most often resulted in potency recovery or improvement, as evidenced by lower MICs and faster bactericidal kinetics in culture media. Best results were obtained after replacement of the N-terminal dipeptide alanine-leucine with heptanoic (C7) or aminododecanoic (NC12) acid. Circular dichroism analysis correlated antibacterial properties to the peptide's secondary structure. MIC experiments and confocal laser scanning microscopy results indicated that C7-S4(3-15) and NC12-S4(3-15) were bactericidal to various oral pathogens, including those which are immobilized in a biofilm. C7-S4(3-15) performed similarly to or better than (depending on growth medium) IB-367, a peptide assessed in clinical trials for treatment of oral mucositis, reducing CFU counts by >3 log units within 2 min of incubation. Collectively, the data indicate that substitution of fatty acids for amino acids may be a useful strategy in revealing improved derivatives of known antimicrobial peptides and suggest the suitability of such compounds for controlling pathogens associated with oral diseases.

* Corresponding author. Mailing address: Department of Biotechnology & Food Engineering, Technion—Israel Institute of Technology, Haifa, Israel. Phone: 972 4 8293340. Fax: 972 4 8293399. E-mail: amor{at}tx.technion.ac.il.

{triangledown} Published ahead of print on 16 October 2006.

Antimicrobial Agents and Chemotherapy, December 2006, p. 4153-4160, Vol. 50, No. 12
0066-4804/06/$08.00+0     doi:10.1128/AAC.00750-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.





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