The Fatty Acid Biosynthesis Enzyme FabI Plays a Key Role in the Development of Liver-Stage Malarial Parasites

Min Yu, T. R.Santha Kumar, Louis J. Nkrumah, Alida Coppi, Silke Retzlaff, Celeste D. Li, Brendan J. Kelly, Pedro A. Moura, Viswanathan Lakshmanan, Joel S. Freundlich, Juan Carlos Valderramos, Catherine Vilcheze, Mark Siedner, Jennifer H.C. Tsai, Brie Falkard, Amar bir Singh Sidhu, Lisa A. Purcell, Paul Gratraud, Laurent Kremer, Andrew P. WatersGuy Schiehser, David P. Jacobus, Chris J. Janse, Arba Ager, William R. Jacobs, James C. Sacchettini, Volker Heussler, Photini Sinnis, David A. Fidock

Research output: Contribution to journalArticle

199 Scopus citations

Abstract

The fatty acid synthesis type II pathway has received considerable interest as a candidate therapeutic target in Plasmodium falciparum asexual blood-stage infections. This apicoplast-resident pathway, distinct from the mammalian type I process, includes FabI. Here, we report synthetic chemistry and transfection studies concluding that Plasmodium FabI is not the target of the antimalarial activity of triclosan, an inhibitor of bacterial FabI. Disruption of fabI in P. falciparum or the rodent parasite P. berghei does not impede blood-stage growth. In contrast, mosquito-derived, FabI-deficient P. berghei sporozoites are markedly less infective for mice and typically fail to complete liver-stage development in vitro. This defect is characterized by an inability to form intrahepatic merosomes that normally initiate blood-stage infections. These data illuminate key differences between liver- and blood-stage parasites in their requirements for host versus de novo synthesized fatty acids, and create new prospects for stage-specific antimalarial interventions.

Original languageEnglish (US)
Pages (from-to)567-578
Number of pages12
JournalCell Host and Microbe
Volume4
Issue number6
DOIs
StatePublished - Dec 11 2008

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All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Virology

Keywords

  • CHEMBIO
  • MICROBIO

Cite this

Yu, M., Kumar, T. R. S., Nkrumah, L. J., Coppi, A., Retzlaff, S., Li, C. D., Kelly, B. J., Moura, P. A., Lakshmanan, V., Freundlich, J. S., Valderramos, J. C., Vilcheze, C., Siedner, M., Tsai, J. H. C., Falkard, B., Sidhu, A. B. S., Purcell, L. A., Gratraud, P., Kremer, L., ... Fidock, D. A. (2008). The Fatty Acid Biosynthesis Enzyme FabI Plays a Key Role in the Development of Liver-Stage Malarial Parasites. Cell Host and Microbe, 4(6), 567-578. https://doi.org/10.1016/j.chom.2008.11.001