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Antimicrobial Agents and Chemotherapy, September 2000, p. 2442-2451, Vol. 44, No. 9
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Antimalarial Activities of Dermaseptin S4 Derivatives

Miriam Krugliak, Rina Feder, Vadim Y. Zolotarev, Leonid Gaidukov, Arie Dagan, Hagai Ginsburg, and Amram Mor*

The Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram 91904 Jerusalem, Israel

Received 27 January 2000/Returned for modification 3 May 2000/Accepted 7 June 2000

The hemolytic antimicrobial peptide dermaseptin S4 was recently shown to exert antimalarial activity. In this study, we attempted to understand the underlying mechanism(s) and identify derivatives with improved antimalarial activity. A number of dermaseptin S4 derivatives inhibited parasite growth with a 50% inhibitory concentration (IC50) in the micromolar range. Among these, the substituted S4 analog K4K20-S4 was the most potent (IC50 = 0.2 µM), while its shorter version, K4-S4(1-13)a, retained a considerable potency (IC50 = 6 µM). Both K4K20-S4 and K4-S4(1-13)a inhibited growth of the parasites more at the trophozoite stage than at the ring stage. Significant growth inhibition was observed after as little as 1 min of exposure to peptides and proceeded with nearly linear kinetics. The peptides selectively lysed infected red blood cells (RBC) while having a weaker effect on noninfected RBC. Thus, K4K20-S4 lysed trophozoites at concentrations similar to those that inhibited their proliferation, but trophozoites were >30-fold more susceptible than normal RBC to the lytic effect of K4K20-S4, the most hemolytic dermaseptin. The same trend was observed with K4-S4(1-13)a. The D isomers of K4K20-S4 or K4-S4(1-13)a were as active as the L counterparts, indicating that antimalarial activity of these peptides, like their membrane-lytic activity, is not mediated by specific interactions with a chiral center. Moreover, dissipation of transmembrane potential experiments with infected cells indicated that the peptides induce damage in the parasite's plasma membrane. Fluorescence confocal microscopy analysis of treated infected cells also indicated that the peptide is able to find its way through the complex series of membranes and interact directly with the intracellular parasite. Overall, the data showed that dermaseptins exert antimalarial activity by lysis of infected cells. Dermaseptin derivatives are also able to disrupt the parasite plasma membrane without harming that of the host RBC.

* 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, September 2000, p. 2442-2451, Vol. 44, No. 9
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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