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Antimicrobial Agents and Chemotherapy, March 2002, p. 689-694, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.689-694.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Antibacterial Properties of Dermaseptin S4 Derivatives with In Vivo Activity

Shiri Navon-Venezia,1 Rina Feder,2 Leonid Gaidukov,2 Yehuda Carmeli,1 and Amram Mor2*

Division of Infectious diseases, Sourasky Medical Center, Tel Aviv,1 The Wolfson Centre for Applied Structural Biology, The Hebrew University of Jerusalem, Givat Ram 91904 Jerusalem, Israel2

Received 24 May 2001/ Returned for modification 29 October 2001/ Accepted 26 November 2001

Derivatives of the cytotoxic peptide dermaseptin S4 have recently emerged as potential antimicrobial agents. Here, we report on the antibacterial properties of three derivatives with improved toxicity profiles: a 28-residues K4K20-S4 and two shorter versions, K4-S4(1-16) and K4-S4(1-13). The range of MICs of K4K20-S4 against clinical isolates of Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli were, respectively, 1 to 4, 1 to 4, and 1 to 16 µg/ml. MICs of the short derivatives were rather similar or two to fourfold higher. Each of the three peptides was rapidly bactericidal in vitro, reducing the number of viable CFU of either E. coli or S. aureus by 6 log units in 30 min or less. Compared with MSI-78 or PG-1, K4-S4(1-13) was at least as potent against bacteria (assessed at two MIC multiples) but displayed lesser toxicity against human erythrocytes. Serial passage in subinhibitory concentrations led to emergence of resistance to commercial antibiotics but not to the L- or D isomer of either of the dermaseptin derivatives. The short derivatives were further investigated for antibacterial activity in vivo, using a peritonitis model of mice infected with P. aeruginosa. Naive mice in the vehicle control group exhibited 75% mortality, compared to 18 or 36% mortality in mice that received a single intraperitoneal injection (4.5 mg/kg) of K4-S4(1-16) or K4-S4(1-13), respectively. In vivo bactericidal activity was confirmed in neutropenic mice, where intraperitoneal administration of K4-S4(1-16) reduced the number of viable CFU in a dose-dependent manner by >3 log units within 1 h of exposure, and this was sustained for at least 5 h. Overall, the data suggest that dermaseptin S4 derivatives could be useful in treatment of infections, including infections caused by multidrug-resistant bacteria.

* Corresponding author. Mailing address: The Laboratory for Antimicrobial Peptides Investigation (L.A.P.I.), The Wolfson Centre for Applied Structural Biology, The Hebrew University of Jerusalem, Givat Ram 91904 Jerusalem, Israel. Phone: (972 2) 65 85 295. Fax: (972 2) 65 85 573. E-mail: amor{at}macbeth.ls.huji.ac.il.

Antimicrobial Agents and Chemotherapy, March 2002, p. 689-694, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.689-694.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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