Effect of a bis-thiazolium compound on the biosynthesis of Plasmodium falciparum phospholipids

Abstract

In the eukaryotic cell, phospholipids can be biosynthesized by two pathways, one from choline and the other one from ethanolamine. The functional effectiveness of each pathway depends on the type of the cell. Thiazolium designed-drugs have shown, under in vivo conditions, antiplasmodial and antimalarial activities with inhibition of the phospholipids biosynthesis. This study aimed to discover the pathways involved in the biosynthesis of phospholipids in Plasmodium and deduce the biochemical steps inhibited by T4, a bis-thiazolium bromide drug. We compared the uptake of radiolabeled precursors and their selective incorporation in the phospholipids of cultured Plasmodium-infected and -uninfected erythrocytes which revealed that phosphatidylcholine of Plasmodium is synthesized both from choline and ethanolamine (4.7 vs 1.9 nmol/10¹⁰ cells.h⁻¹). T4 has no effect on the biosynthesis of phosphatidylethanolamine but T4 inhibited, in a selective way, the in vitro uptake of choline. However no enzymes in the biosynthesis of phospholipids seem to be inhibited by T4 but rather an inhibition of choline entry into the parasite.

Keywords::

• drug effect
• metabolism
• Plasmodium falciparum
• phosphatidylcholine
• phosphatidylethanolamine
• T4
• inhibition

Acknowledgement

The authors acknowledge S Wein, M Maynadier, F Boudou for their technical assistances. We thank S Herbute K, Wengelnick and H Vial at the Laboratory of “Dynamique des Interactions Membranaires Normales et Pathologiques” (CNRS UMR 5235) University of Montpellier II for their technical assistance and helpful advice concerning the protocol of experiments.

We acknowledge M. Calas at the Laboratory of “Amino-acides Peptides et Protéines” (CNRS UMR 5810) for providing stocks of T4.

Declaration of interest: The authors report no conflicts of interest.