Malaria affects 500 million people each year, causing more than 2 million deaths mainly children living in sub-Saharan Africa. Because of the rise and spread of drug resistance to current antimalarials, new drug targets need. The widely used quinolines and artemisinin classes of antimalarials interfere with metal metabolism to kill the malaria parasite, Plasmodium falciparum. Many metal chelators for example deferoxamine, an intravenous clinical iron chelator, also kill the parasite. The broad long-term objective of this proposal is to enhance metal chelation therapy by characterization of their perturbation of metal ion homeostasis in Plasmodium falciparum. This proposal will investigate the global response to metal chelation in Plasmodium falciparum while focusing on zinc and the characterization of a putative zinc transporter. The hypothesis is alteration of zinc metabolism by zinc chelation will be an effective chemotherapeutic target. The specific research aims are 1) to compare the effects of zinc chelation both on stage-specific global gene transcription in Plasmodium falciparum by microarray analysis and also on the metabolome using mass spectroscopic analysis; 2) to characterize the function of a P. falciparum zinc transporter by yeast complementation and/or heterologous expression in Xenopus oocytes and 3) to localize the membrane compartment for the zinc transporter.
