Journal
CELL HOST & MICROBE
Volume 4, Issue 6, Pages 567-578Publisher
CELL PRESS
DOI: 10.1016/j.chom.2008.11.001
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Funding
- National Institutes of Health [P01 AI060342, R01 A1056840]
- Medicines for Malaria Venture
- Deutsche Forschungsgesellschaft (DFG) [4497/1-2]
- Ministere de I'Education Nationale de la Recherche et des Technologies
- Centre National de la Recherche Scientifique
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The fatty acid synthesis type 11 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 Fabl. Here, we report synthetic chemistry and transfection studies concluding that Plasmodium Fabl is not the target of the antimalarial activity of triclosan, an inhibitor of bacterial Fabl. Disruption of fabl in P. falciparum or the rodent parasite P. berghei does not impede blood-stage growth. In contrast, mosquito-derived, Fabl-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.
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