Genetic linkage of pfmdr1 with food vacuolar solute import in Plasmodium falciparum

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Abstract
The P‐glycoprotein homolog of the human malaria parasite Plasmodium falciparum (Pgh‐1) has been implicated in decreased susceptibility to several antimalarial drugs, including quinine, mefloquine and artemisinin. Pgh‐1 mainly resides within the parasite's food vacuolar membrane. Here, we describe a surrogate assay for Pgh‐1 function based on the subcellular distribution of Fluo‐4 acetoxymethylester and its free fluorochrome. We identified two distinct Fluo‐4 staining phenotypes: preferential staining of the food vacuole versus a more diffuse staining of the entire parasite. Genetic, positional cloning and pharmacological data causatively link the food vacuolar Fluo‐4 phenotype to those Pgh‐1 variants that are associated with altered drug responses. On the basis of our data, we propose that Pgh‐1 imports solutes, including certain antimalarial drugs, into the parasite's food vacuole. The implications of our findings for drug resistance mechanisms and testing are discussed.