Characterization of the choline carrier of Plasmodium falciparum: a route for the selective delivery of novel antimalarial drugs

New drugs are urgently needed to combat the growing problem of drug resistance in Plasmodium falciparum malaria. The infected erythrocyte is a multicompart-mental system, and its transporters are of interest as drug targets in their own right and as potential routes for the delivery of antimalarial drugs. Choline is an impor-tant nutrient that penetrates infected erythrocyte membranes through the en-dogenous carrier and through parasite-induced permeability pathways, but noth-ing is known about its transport into the intracellular parasite. Here we present the first characterization of choline transport across the parasite membrane. Transport exhibits Michaelis-Menten kinetics with an apparent Km of 25.0 3.5 M for cho-line. The carrier is inhibitor-sensitive, tem-perature-dependent, and Na-indepen-dent, and it is driven by the proton-motive force. Highly active bis-amidine and bis-quaternary ammonium compounds are also known to penetrate the host erythro-cyte membrane through parasite-induced permeability pathways. Here, we demon-strate that the parasite choline trans-porter mediates the delivery of these com-pounds to the intracellular parasite. Thus, the induced permeability pathways in the host erythrocyte membrane and the para-site choline transporter described here form a cooperative transport system that shows great promise for the selective targeting of new agents for the chemo-therapy of malaria. (Blood. 2004;104