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, Hugues Ahiboh, Duk Won D. Chung, Jacques Prudhomme, David Plouffe, Kerstin Henson, Yingyao Zhou, William Witola, John R. Yates, Choukri Ben Mamoun, Elizabeth A. Winzeler, Henri Vial

Research output: Research - peer-reviewArticle

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.

LanguageEnglish (US)
Article number513
JournalBMC Genomics
Volume9
DOIs
StatePublished - Oct 30 2008
Externally publishedYes

Fingerprint

Falciparum Malaria
Choline
Parasites
1,12-bis(4-methyl-5-(2-methoxyethyl)thiazol-3-ium-3-yl)dodecane
Ethanolamine
Plasmodium falciparum
Phosphatidylcholines
Pharmaceutical Preparations
Gene Expression Profiling
Proteome
Cell Cycle Checkpoints
Lipid Metabolism
Proteomics
Phosphotransferases
Clone Cells
Enzymes
Genes
Metabolic Side Effects of Drugs and Substances

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

Cite this

Le Roch, K. G., Johnson, J. R., Ahiboh, H., Chung, D. W. D., Prudhomme, J., Plouffe, D., ... Vial, H. (2008). A systematic approach to understand the mechanism of action of the bisthiazolium compound T4 on the human malaria parasite, Plasmodium falciparum. BMC Genomics, 9, [513]. DOI: 10.1186/1471-2164-9-513

A systematic approach to understand the mechanism of action of the bisthiazolium compound T4 on the human malaria parasite, Plasmodium falciparum. / Le Roch, Karine G.; Johnson, Jeffrey R.; Ahiboh, Hugues; Chung, Duk Won D.; Prudhomme, Jacques; Plouffe, David; Henson, Kerstin; Zhou, Yingyao; Witola, William; Yates, John R.; Mamoun, Choukri Ben; Winzeler, Elizabeth A.; Vial, Henri.

In: BMC Genomics, Vol. 9, 513, 30.10.2008.

Research output: Research - peer-reviewArticle

Le Roch, KG, Johnson, JR, Ahiboh, H, Chung, DWD, Prudhomme, J, Plouffe, D, Henson, K, Zhou, Y, Witola, W, Yates, JR, Mamoun, CB, Winzeler, EA & Vial, H 2008, 'A systematic approach to understand the mechanism of action of the bisthiazolium compound T4 on the human malaria parasite, Plasmodium falciparum' BMC Genomics, vol 9, 513. DOI: 10.1186/1471-2164-9-513
Le Roch KG, Johnson JR, Ahiboh H, Chung DWD, Prudhomme J, Plouffe D 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 Oct 30;9. 513. Available from, DOI: 10.1186/1471-2164-9-513
Le Roch, Karine G. ; Johnson, Jeffrey R. ; Ahiboh, Hugues ; Chung, Duk Won D. ; Prudhomme, Jacques ; Plouffe, David ; Henson, Kerstin ; Zhou, Yingyao ; Witola, William ; Yates, John R. ; Mamoun, Choukri Ben ; Winzeler, Elizabeth A. ; Vial, Henri. / A systematic approach to understand the mechanism of action of the bisthiazolium compound T4 on the human malaria parasite, Plasmodium falciparum. In: BMC Genomics. 2008 ; Vol. 9.
@article{0e1e22c88d604b8e8f5fbf06f48bd133,
title = "A systematic approach to understand the mechanism of action of the bisthiazolium compound T4 on the human malaria parasite, Plasmodium falciparum",
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.",
author = "{Le Roch}, {Karine G.} and Johnson, {Jeffrey R.} and Hugues Ahiboh and Chung, {Duk Won D.} and Jacques Prudhomme and David Plouffe and Kerstin Henson and Yingyao Zhou and William Witola and Yates, {John R.} and Mamoun, {Choukri Ben} and Winzeler, {Elizabeth A.} and Henri Vial",
year = "2008",
month = "10",
doi = "10.1186/1471-2164-9-513",
volume = "9",
journal = "BMC Genomics",
issn = "1471-2164",
publisher = "BioMed Central",

}

TY - JOUR

T1 - A systematic approach to understand the mechanism of action of the bisthiazolium compound T4 on the human malaria parasite, Plasmodium falciparum

AU - Le Roch,Karine G.

AU - Johnson,Jeffrey R.

AU - Ahiboh,Hugues

AU - Chung,Duk Won D.

AU - Prudhomme,Jacques

AU - Plouffe,David

AU - Henson,Kerstin

AU - Zhou,Yingyao

AU - Witola,William

AU - Yates,John R.

AU - Mamoun,Choukri Ben

AU - Winzeler,Elizabeth A.

AU - Vial,Henri

PY - 2008/10/30

Y1 - 2008/10/30

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=57449114130&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=57449114130&partnerID=8YFLogxK

U2 - 10.1186/1471-2164-9-513

DO - 10.1186/1471-2164-9-513

M3 - Article

VL - 9

JO - BMC Genomics

T2 - BMC Genomics

JF - BMC Genomics

SN - 1471-2164

M1 - 513

ER -