Artemisinin and its derivatives are transported by a vacuolar-network of Plasmodium falciparum and their anti-malarial activities are additive with toxic sphingolipid analogues that block the network.
There is great need to identify and characterize drug targets and chemotherapeutic strategies against malaria. Here we show that a vacuolar-network induced by the human malaria parasite Plasmodium falciparum, is a major import pathway for artemisinin, a leading, new anti-malarial that is known to be effective against drug resistant strains. We also show that artemisinin-treatment induces aberrant, budding of a vacuolar-network membrane protein and its antimalarial activity is additive with toxic sphingolipid analogues that block the network. The data suggest that artemisinin alters membrane protein export from the vacuolar-network and combinations with anti-network reagents have the potential to provide powerful new chemotherapy for drug resistant malaria.
Department of Microbiology and Immunology, Stanford University School of Medicine, CA 94305-5402, USA.
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T
Akompong
J
J
VanWye
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N
Ghori
K
K
Haldar
D000818:Animals; D000962:Antimalarials / Q000378:metabolism* / Q000494:pharmacology; D037621:Artemisinins; D001692:Biological Transport; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance; D004357:Drug Synergism; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology; D008565:Membrane Proteins / Q000378:metabolism; D008854:Microscopy, Electron; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism*; D015800:Protozoan Proteins / Q000378:metabolism; D012717:Sesquiterpenes / Q000378:metabolism* / Q000494:pharmacology; D013107:Sphingolipids / Q000494:pharmacology*; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism*
D000962:Antimalarials; D037621:Artemisinins; D008565:Membrane Proteins; D015800:Protozoan Proteins; D012717:Sesquiterpenes; D013107:Sphingolipids; D002738:Chloroquine; C031327:artemisinin