Research article

A systematic approach to understand the mechanism of action of the bisthiazolium compound T4 on the human malaria parasite, Plasmodium falciparum

Karine G Le Roch¹ , Jeffrey R Johnson² , Hugues Ahiboh³ , Duk-Won D Chung¹ , Jacques Prudhomme¹ , David Plouffe⁴ , Kerstin Henson² , Yingyao Zhou⁴ , William Witola⁵ , John R Yates² , Choukri Ben Mamoun⁵ , Elizabeth A Winzeler^2,4 and Henri Vial³

¹Department of Cell Biology and Neuroscience, University of California, Riverside, 900 University Avenue, Riverside, CA, 92521 USA

²Department of Cell Biology ICND202, the Scripps Research Institute, 10550 North Torrey Pines Rd, La Jolla, CA, 92037, USA

³Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université Montpellier II, Place Eugène Bataillon, 34095 Montpellier Cedex 05, France

⁴Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA, 92121, USA

⁵Department of Genetics and Developmental Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030-3301, USA

author email corresponding author email

BMC Genomics 2008, 9:513doi:10.1186/1471-2164-9-513

Published:	30 October 2008

Abstract

Background

In recent years, a major increase in the occurrence of drug resistant falciparum malaria has been reported. Choline analogs, such as the bisthiazolium T4, represent a novel class of compounds with strong potency against drug sensitive and resistant P. falciparum clones. Although T4 and its analogs are presumed to target the parasite's lipid metabolism, their exact mechanism of action remains unknown. Here we have employed transcriptome and proteome profiling analyses to characterize the global response of P. falciparum to T4 during the intraerythrocytic cycle of this parasite.

Results

No significant transcriptional changes were detected immediately after addition of T4 despite the drug's effect on the parasite metabolism. Using the Ontology-based Pattern Identification (OPI) algorithm with an increased T4 incubation time, we demonstrated cell cycle arrest and a general induction of genes involved in gametocytogenesis. Proteomic analysis revealed a significant decrease in the level of the choline/ethanolamine-phosphotransferase (PfCEPT), a key enzyme involved in the final step of synthesis of phosphatidylcholine (PC). This effect was further supported by metabolic studies, which showed a major alteration in the synthesis of PC from choline and ethanolamine by the compound.

Conclusion

Our studies demonstrate that the bisthiazolium compound T4 inhibits the pathways of synthesis of phosphatidylcholine from choline and ethanolamine in P. falciparum, and provide evidence for post-transcriptional regulations of parasite metabolism in response to external stimuli.