Selective killing of the human malaria parasite Plasmodium falciparum by a benzylthiazolium dye.
Malaria is an infectious disease caused by protozoan parasites of the genus Plasmodium. The most virulent form of the disease is caused by Plasmodium falciparum which infects hundreds of millions of people and is responsible for the deaths of 1-2 million individuals each year. An essential part of the parasitic process is the remodeling of the red blood cell membrane and its protein constituents to permit a higher flux of nutrients and waste products into or away from the intracellular parasite. Much of this increased permeability is due to a single type of broad specificity channel variously called the new permeation pathway (NPP), the nutrient channel, and the Plasmodial surface anion channel (PSAC). This channel is permeable to a range of low molecular weight solutes both charged and uncharged, with a strong preference for anions. Drugs such as furosemide that are known to block anion-selective channels inhibit PSAC. In this study, we have investigated a dye known as benzothiocarboxypurine, BCP, which had been studied as a possible diagnostic aid given its selective uptake by P. falciparum infected red cells. We found that the dye enters parasitized red cells via the furosemide-inhibitable PSAC, forms a brightly fluorescent complex with parasite nucleic acids, and is selectively toxic to infected cells. Our study describes an antimalarial agent that exploits the altered permeability of Plasmodium-infected red cells as a means to killing the parasite and highlights a chemical reagent that may prove useful in high throughput screening of compounds for inhibitors of the channel.
Kelly
Jane X
JX
Medical Research Service, RD-33, Department of Veterans Affairs Medical Center, 3710 SW U.S. Veterans Hospital Road, Portland, OR 97239, and Department of Chemistry, Portland State University, Portland, OR 97207-0751, USA.
Winter
Rolf W
RW
Braun
Theodore P
TP
Osei-Agyemang
Myralyn
M
Hinrichs
David J
DJ
Riscoe
Michael K
MK
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D004396:Coloring Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D016778:Malaria, Falciparum / Q000175:diagnosis / Q000188:drug therapy / Q000469:parasitology; D018613:Microscopy, Confocal; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D011687:Purines / Q000138:chemical synthesis / Q000494:pharmacology*
D000962:Antimalarials; D004396:Coloring Agents; D011687:Purines; C067493:benzothiocarboxypurine