The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites.
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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.
Yu, M., Kumar, T., Nkrumah, L. J., Coppi, A., Retzlaff, S., Li, C. D., ... Fidock, D. A.
complete list of authors
Yu, Min||Kumar, TR Santha||Nkrumah, Louis J||Coppi, Alida||Retzlaff, Silke||Li, Celeste D||Kelly, Brendan J||Moura, Pedro A||Lakshmanan, Viswanathan||Freundlich, Joel S||Valderramos, Juan-Carlos||Vilcheze, Catherine||Siedner, Mark||Tsai, Jennifer H-C||Falkard, Brie||Sidhu, Amar Bir Singh||Purcell, Lisa A||Gratraud, Paul||Kremer, Laurent||Waters, Andrew P||Schiehser, Guy||Jacobus, David P||Janse, Chris J||Ager, Arba||Jacobs, William R||Sacchettini, James C||Heussler, Volker||Sinnis, Photini||Fidock, David A