Ionophore-phospholipid interactions in Langmuir films in relation to ionophore selectivity toward plasmodium-infected erythrocytes

Carboxylic true ionophores were previously demonstrated to have efficient a ntimalarial activity against the human parasite Plasmodium falciparum, with a 50% inhibitory concentration around nM and generally high selectivity as compared to their toxic effects against mammalian cell lines. The decrease d molecular packing of the erythrocyte membrane outer leaflet after malaria l infection could explain the preferential ionophore interaction with infec ted erythrocytes. Monolayer penetration experiments using different phospho lipid films showed strong incorporation of true carboxylic ionophores, from classes 1 (nigericin) and 2 (lasalocid), up to a surface pressure close to film collapse. The interaction was slightly higher with PC (phosphatidylch oline) monolayers than with monolayers composed of cholesterol-containing t otal lipid extracts from either malaria-infected or normal erythrocytes, an d the two latter induced identical interactions with 5-bromo lasalocid, Sur face pressure-area isotherms for pure ionophores on water and surface tensi on of ionophore aqueous solutions clearly highlighted the surface-active ch aracteristics of these ionophores and allowed determination of their molecu lar area in compact monolayers, The estimated ionophore concentration in th e mixed interfacial layers indicates that higher amounts (threefold more) o f ionophores might be integrated in infected erythrocyte membrane due to th eir impaired molecular packing as compared to normal erythrocytes. This inf ection-enhanced penetration efficiency does not appear directly related to the change in erythrocyte membrane lipid composition, but it could be the b asis of ionophore selectivity for infected erythrocytes. (C) 1999 Academic Press.