Abstract
The plasmodial surface anion channel (PSAC) increases erythrocyte permeability to many solutes in malaria but has uncertain physiological significance. We used a PSAC inhibitor with different efficacies against channels from two Plasmodium falciparum parasite lines and found concordant effects on transport and in vitro parasite growth when external nutrient concentrations were reduced. Linkage analysis using this growth inhibition 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 between the clag3 genes, indicated that the inhibitor kills parasites 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 increase the diversity of available channel isoforms. Broad-spectrum inhibitors, which presumably interact with conserved sites on the channel, also exhibited improved efficacy with nutrient restriction. These findings indicate that PSAC functions in nutrient acquisition for intracellular parasites. Although key questions regarding the channel and its biological role remain, antimalarial drug development targeting PSAC should be pursued.
Footnotes
↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This research was supported by the Medicines for Malaria Venture and the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. A.D.P. and S.A.D. are named inventors on provisional patent applications describing some of the PSAC inhibitors reported in this article. M.M.B., S.T.N., N.P.P., and T.L.B. are employees and shareholders of Microbiotix, Inc., which has obtained a license to develop PSAC inhibitors as antimalarial drugs.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS:
- PSAC
- plasmodial surface anion channel
- RT
- reverse transcription
- PCR
- polymerase chain reaction
- ISPA
- isolate-specific plasmodial surface anion channel antagonist
- PGIM
- plasmodial surface anion channel growth inhibition medium
- QTL
- quantitative trait locus
- MTS
- 3-(4,5-dimethylthiazol-2-yl)- 5-(3-carboxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt.
- Received July 13, 2012.
- Accepted September 4, 2012.
- U.S. Government work not protected by U.S. copyright
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