Title

Role of Plasmodium falciparum Phosphoethanolamine Methyltransferase in Parasite Development and Differentiation

Date of Completion

January 2011

Keywords

Biology, Microbiology

Degree

Ph.D.

Abstract

Plasmodium falciparum is an intra-erythrocytic parasite that causes the human disease, malaria. Current antimalarial therapies target the asexual intra-erythrocytic stages of the parasite, preventing clinical manifestations of the disease, but failing to block gametocyte differentiation a key stage for transmission of the disease. The development of drug resistance to most of the currently available antimalarials has created an urgent need for the identification of novel chemical compounds, and for the discovery of new biological pathways in the parasite to be used as targets in antimalarial therapy. Phospholipid synthesis pathways in the parasite have shown to be promising targets for antimalarial drug development. P. falciparum phosphoethanolamine methyltransferase, PfPMT is an enzyme that is unique to human malaria parasites, nematodes, and plants, but absent in humans. PfPMT catalyzes the methylation of phosphoethanolamine to phosphocholine, which feeds into the CDP-choline pathway synthesizing the essential phospholipid, phosphatidylcholine. ^ Genetic disruption of the Pfpmt gene results in a severe growth defect in asexual parasite development. But more importantly we found that P. falciparum parasites lacking PIPMT were unable to undergo gametocyte differentiation. This finding suggests that PfPMT is essential for gametocyte development and could be a target for the development of transmission blocking drugs.^ An in vitro enzyme-coupled spectrophotometeric assay was developed for the identification of inhibitors of PfPMT activity. Surprisingly we found the known antimalarial drug amodiaquine to be a strong inhibitor of PfPMT activity. Using this assay to screen a small chemical compound library, we found eleven compounds to inhibit PfPMT activity and asexual parasite replication in the low micromolar range. Two of these compounds were also found to inhibit gametocyte differentiation.^ With the current status of today's antimalarials, there is a great need for new compounds that can inhibit both infection and transmission. Our analysis of PfPMT and its role in asexual development and sexual differentiation have led us to conclude that PfPMT is a valuable drug target. Additionally we've identified novel compounds that could be used as leads in the development of new antimalarial drugs. ^