Antiplasmodial activity of the
dermaseptin S4 derivative K(4)S4(1-13) (P) was shown to be mediated by lysis of the host cells. To identify antiplasmodial
peptides with enhanced selectivity, we produced and screened new derivatives based on P and singled out the aminoheptanoylated
peptide (NC7-P) for its improved antiplasmodial properties. Compared with P, NC7-P displayed both increased
antiparasitic efficiency and reduced
hemolysis, including against infected cells. Antiplasmodial activity of P and its derivative was time-dependent and irreversible, implying a cytotoxic effect. But, whereas the dose dependence of growth inhibition and
hemolysis of infected cells overlapped when treated with P, NC7-P exerted more than 50% growth inhibition at
peptide concentrations that did not cause
hemolysis. Noticeably, NC7-P but not P, dissipated the parasite plasma membrane potential and caused depletion of intraparasite
potassium at nonhemolytic conditions. Confocal microscopy analysis of infected cells localized the rhodaminated derivative in association with parasite membranes and intraerythrocytic tubulovesicular structures, whereas in normal cells, the
peptide localized exclusively at the plasma membrane. Overall, the data demonstrate that
antimicrobial peptides can be engineered to act specifically on the membrane of intracellular parasites and support a mechanism whereby NC7-P crosses the host cell plasma membrane and disrupts the parasite membrane(s).