Solute Restriction Reveals an Essential Role for clag3- Associated Channels in Malaria Parasite Nutrient Acquisition□S

The plasmodial surface anion channel (PSAC) increases eryth-rocyte permeability to many solutes in malaria but has uncertain physiological significance. We used a PSAC inhibitor with dif-ferent efficacies against channels from two Plasmodium falci-parum parasite lines and found concordant effects on transport and in vitro parasite growth when external nutrient concentra-tions were reduced. Linkage analysis using this growth inhibi-tion phenotype in the Dd2 HB3 genetic cross mapped the clag3 genomic locus, consistent with a role for two clag3 genes in PSAC-mediated transport. Altered inhibitor efficacy, achieved through allelic exchange or expression switching be-tween the clag3 genes, indicated that the inhibitor kills para-sites through direct action on PSAC. In a parasite unable to undergo expression switching, the inhibitor selected for ectopic homologous recombination between the clag3 genes to in-crease the diversity of available channel isoforms. Broad-spec-trum inhibitors, which presumably interact with conserved sites on the channel, also exhibited improved efficacy with nutrient restriction. These findings indicate that PSAC functions in nu-trient acquisition for intracellular parasites. Although key ques-tions regarding the channel and its biological role remain, an-timalarial drug development targeting PSAC should be pursued