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.