The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites

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...

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Published in:	Cell host & microbe Vol. 4; no. 6; pp. 567 - 578
Main Authors:	Yu, Min, Kumar, T R 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, Jr, William R, Sacchettini, James C, Heussler, Volker, Sinnis, Photini, Fidock, David A
Format:	Journal Article
Language:	English
Published:	United States Elsevier 11-12-2008
Subjects:	Animals Antimalarials Antimalarials - pharmacology Biochemistry, Molecular Biology Gene Deletion Life Sciences Liver Liver - parasitology Malaria Malaria - parasitology Mice Mice, Inbred C57BL Mutagenesis, Insertional Parasitemia Plasmodium berghei Plasmodium berghei - enzymology Plasmodium berghei - growth & development Plasmodium berghei - pathogenicity Plasmodium falciparum Plasmodium falciparum - enzymology Plasmodium falciparum - growth & development Plasmodium falciparum - pathogenicity Protozoan Proteins Protozoan Proteins - genetics Protozoan Proteins - metabolism Triclosan Triclosan - pharmacology
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC2646117 Current Address: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA These authors contributed equally to this work. Current Address: Regeneron, Tarrytown, NY 10591, USA
ISSN:	1931-3128 1934-6069
DOI:	10.1016/j.chom.2008.11.001