The antimicrobial peptide NK-2, the core region of mammalian NK-lysin, kills intraerythrocytic Plasmodium falciparum

In a time of dramatically increasing resistance of microbes to all kinds of antibiotics, natural antimicrobial peptides and synthetic analogs thereof have emerged as compounds with potentially significant therapeutical applications against human pathogens. Only very few of these peptide antibiotics have been tested against protozoan pathogens that are a major cause of morbidity and mortality in large parts of the world. Here, we studied the effect of NK-2, a peptide representing the cationic core region of the lymphocytic effector protein NK-lysin, on the malaria parasite Plasmodium falciparum. Whereas noninfected red blood cells were hardly affected, human erythrocytes infected with the parasite were rapidly permeabilized by NK-2 in the micromolar range. Loss of plasma membrane asymmetry and concomitant exposure of phosphatidylserine upon infection appears to be the molecular basis for the observed target preference of NK-2, as can be demonstrated by annexin V binding. The peptide also affects the viability of the intracellular parasite, as evidenced by the drop in DNA content of cultured parasites. Accumulated evidence derived from permeabilization assays using parasites and liposomes as targets and from fluorescence microscopy of infected erythrocytes treated with fluorescently labeled NK-2 indicates that the positively charged peptide electrostatically interacts with the altered and negatively charged plasma membrane of the infected host cell and traverses this membrane as well as the parasitophorous vacuole membrane to reach its final target, the intracellular parasite. The apparent affinity for foreign membranes that resulted in the death of a eukaryotic parasite residing in human host cells makes NK-2 a promising template for novel anti-infectives.