PROTEIN SYNTHESIS AND DEVELOPMENTAL TRANSITIONS IN PLASMODIUM

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Abstract

We have shown that thiopeptides selectively interact with the plastid-like organelle of P. falciparum, presumably through interaction with the GTPase-binding domain of the organellar large subunit ribosomal RNA. In this report, we investigate the effects of different thiopeptides on the process of transmission through mosquitoes and the development of early erythrocytic stages in the mammalian host. Preincubation of mature, infective sporozoites with thiostrepton has no observable effect on their infectivity. Plasmodium berghei infection by the bite of infected mosquitoes was, however, prevented by pretreatment of mice with thiostrepton. This would indicate that the plastid function is crucial for parasite development in the liver. Blood stage infections of P. berghei were cleared with drug treatment. Clearance of the parasite from the blood followed the delayed kinetics associated with drugs that interact with the apicoplast. Thiostrepton treatment of infected mice reduced transmission of parasites into the mosquito by over ten fold. This indicates that the plastid function is also crucial during the sexual development of the parasite. Drugs targeting the plastid are therefore useful prophylactically, as a curative and in blocking transmission of the parasite. We find that treatment with thiostrepton itself has side effects when used at high does (500 mg/kg) resulting in anemia and discomfort in the mice. The negative effects seen on the mice, however, suggest that other commercially unavailable thiopeptides should be produced and tested in vivo. For example micrococcin, that has been shown to act in vitro at one hundred fold lower doses than thiostrepton, is commercially unavailable, but seems to have great potential as an antimalarial drug. These results indicate that plastid function is critical during a large portion of the parasite's life cycle.