ANTIMALARIAL ACTION AND RESISTANCE

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With 200-300 million cases and 2-3 million deaths each year, malaria is of overwhelming medical importance. The treatment and prevention of malaria due to Plasmodium falciparum is complicated by resistance to chloroquine (in South America, Southeast Asia and Africa), and by the absence of defined molecular targets for antimalarial action. The specific aims of these studies are to: 1) define the molecule(s) responsible for chloroquine efflux and thus for chloroquine resistance in P. falciparum, 2) define the molecule(s) responsible for chloroquine accumulation and thus for susceptibility to chloroquine in P. falciparum, and 3) develop structure-activity relationships for the quinoline antimalarials. A cross between chloroquine-resistant and susceptible P. falciparum will be used to identify the gene(s) responsible for chloroquine-resistance. To accomplish this, a genomic DNA library from the resistant Dd2 parent strain will be hybridized to DNA from the resistant progeny. Based on this information peptides will be synthesized and used to produce antibodies to test for the gene product in resistant and susceptible strains. The molecule(s) responsible for chloroquine accumulation will be identified by its ability to bind chloroquine using: gel electrophoresis and autoradiography, chloroquine-- sepharose column chromatography, inhibition of chloroquine accumulation by antibodies to a reconstituted vesicle preparation, and photoactivatable cross-linking reagents. To develop structure-activity linking relationships, quinoline analogs with specific structural modifications will be tested for their ability to inhibit chloroquine accumulation by the reconstituted vesicle preparation and for antiplasmodial activity against chloroquine-susceptible and resistant strains. The broad long-term goal of these studies is to provide a rational basis for the development of antimalarials active against multiply-resistant P. falciparum.