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

Karine G Le Roch , Jeffrey R Johnson (1, 2, 3) , Hugues Ahiboh , Duk-Won D Chung , Jacques Prudhomme (4) , David Plouffe , Kerstin Henson , Yingyao Zhou (5, 6, 7) , William Witola , John R Yates (8) , Choukri Ben Mamoun , Elizabeth A Winzeler , Henri Vial (9, 10)

1 instituto Geofísico
2 BAS - British Antarctic Survey
3 J Craig Venter Institute
4 CGPhiMC - Centre de génétique et de physiologie moléculaire et cellulaire
5 Cold and Arid Regions Environmental and Engineering Research Institute
6 Department of Ecology and Evolutionary Biology
7 NIT - Ningbo Institute of Technology
8 The Scripps Research Institute [La Jolla, San Diego]
9 DIMNP - Dynamique des interactions membranaires normales et pathologiques
10 DMIM - Dynamique moléculaire des interactions membranaires

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.

Domaines: Biochimie, Biologie Moléculaire

Karine G Le Roch, Jeffrey R Johnson, Hugues Ahiboh, Duk-Won D Chung, Jacques Prudhomme, et al.. A systematic approach to understand the mechanism of action of the bisthiazolium compound T4 on the human malaria parasite, Plasmodium falciparum.. BMC Genomics, 2008, 9, pp.513. ⟨10.1186/1471-2164-9-513⟩. ⟨hal-00374517⟩