Jk. Ghosh et al., SELECTIVE CYTOTOXICITY OF DERMASEPTIN S3 TOWARD INTRAERYTHROCYTIC PLASMODIUM-FALCIPARIUM AND THE UNDERLYING MOLECULAR-BASIS, The Journal of biological chemistry, 272(50), 1997, pp. 31609-31616
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 hemo
lytic peptide dermaseptin S4 (DS4) and the nonhemolytic peptide dermas
eptin S3 (DS3) toward human erythrocytes infected by the malaria paras
ite Plasmodium falciparum. Both DS4 and DS3 inhibited the parasite's a
bility to incorporate [H-3]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 mechan
ism of this selective cytotoxicity, we labeled the peptides with fluor
escent probes and investigated their organization in solution and in m
embranes. In Plasmodium-infected cells, rhodamine-labeled peptides int
eracted directly with the intracellular parasite, in contrast to nonin
fected cells, where the peptides remained bound to the erythrocyte pla
sma membrane. Binding experiments to phospholipid membranes revealed t
hat DS3 and DS4 had similar binding characteristics. Membrane permeati
on studies indicated that the peptides were equally potent in permeati
ng phosphatidylserine/phosphatidylcholine vesicles, whereas DS4 was mo
re 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 wi
th vesicles, albeit with different kinetics. In light of these results
, we propose a mechanism by which dermaseptins permeate cells and affe
ct intraerythrocytic parasites.