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Volume 272, Number 50, Issue of December 12, 1997 pp. 31609-31616

Selective Cytotoxicity of Dermaseptin S3 toward Intraerythrocytic Plasmodium falciparum and the Underlying Molecular Basis

(Received for publication, July 28, 1997, and in revised form, September 8, 1997)

Jimut Kanti Ghosh , Dan Shaool ^¶ , Philippe Guillaud ^¶ , Liliane Cicéron , Dominique Mazier , Irina Kustanovich ^** , Yechiel Shai and Amram Mor ^**

From the  Department of Membrane Research and Biophysics, The Weizmann Institute of Science, Rehovot 76100, Israel, ^¶ Service Imagerie, Institut Jacques Monod, 2 Place Jussieu, 75251 Paris Cedex 05, France,  INSERM U313, Faculté de Médecine Pitié-Salpêtrière, 75634 Paris Cedex 13, France, and ^** The Wolfson Center for Applied Structural Biology, The Hebrew University of Jerusalem, Givat Ram 91904, Jerusalem, Israel

The antimicrobial activity of various naturally occurring microbicidal peptides was reported to result from their interaction with microbial membrane. In this study, we investigated the cytotoxicity of the hemolytic peptide dermaseptin S4 (DS4) and the nonhemolytic peptide dermaseptin S3 (DS3) toward human erythrocytes infected by the malaria parasite Plasmodium falciparum. Both DS4 and DS3 inhibited the parasite's ability to incorporate [³H]hypoxanthine. However, while DS4 was toxic toward both the parasite and the host erythrocyte, DS3 was toxic only toward the intraerythrocytic parasite. To gain insight into the mechanism of this selective cytotoxicity, we labeled the peptides with fluorescent probes and investigated their organization in solution and in membranes. In Plasmodium-infected cells, rhodamine-labeled peptides interacted directly with the intracellular parasite, in contrast to noninfected cells, where the peptides remained bound to the erythrocyte plasma membrane. Binding experiments to phospholipid membranes revealed that DS3 and DS4 had similar binding characteristics. Membrane permeation studies indicated that the peptides were equally potent in permeating phosphatidylserine/phosphatidylcholine vesicles, whereas DS4 was more permeative with phosphatidylcholine vesicles. In aqueous solutions, DS4 was found to be in a higher aggregation state. Nevertheless, both DS3 and DS4 spontaneously dissociated to monomers upon interaction with vesicles, albeit with different kinetics. In light of these results, we propose a mechanism by which dermaseptins permeate cells and affect intraerythrocytic parasites.

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