Phospholipid metabolism as a new target for malaria chemotherapy. Mechanism of action of D-2-amino-1-butanol.

A number of choline and ethanolamine analogs were evaluated as inhibitors of P. falciparum growth in vitro. 1-Aziridineethanol, DL-2-amino-1,3-propranediol and D- or L-2-amino-1-butanol were the most efficient inhibitors of parasite multiplication, with an IC50 of 50-80 microM, whereas numerous other analogs were less active. The effect of D-2-amino-1-butanol on various metabolisms of P. knowlesi-infected simian erythrocytes was studied by incubating these cells with different labeled precursors of phospholipids, nucleic acids, proteins, and with radioactive glucose. In the presence of radioactive glycerol, oleate or lysophosphatidylcholine, the appearance of radioactivity in an unnatural phospholipid indicated that 2-aminobutanol was incorporated into a new PL which accounted for up to 30-40% of the total biosynthesized lipids. This new phospholipid accumulated primarily at the expense of PE biosynthesis and decreased the decarboxylation of phosphatidylserine. These effects were not accompanied, over a large range of concentrations, by any parallel change in nucleic or protein synthesis, nor in glucose metabolism. These data demonstrate that the incorporation of analogs, instead of the natural polar head groups, into cellular phospholipids, and/or modification of phospholipid composition have a deleterious impact on the growth of Plasmodium. It follows that PL metabolism is a crucial process for Plasmodium growth and may constitute a potentially fruitful chemotherapeutic approach to malaria.