title: The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites.
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.
authors.affiliation: Department of Microbiology, Columbia University, New York, NY 10032, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.forename: T R Santha
authors.initials: TR
authors.lastname: Kumar
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Nkrumah
authors.forename: Alida
authors.initials: A
authors.lastname: Coppi
authors.forename: Silke
authors.initials: S
authors.lastname: Retzlaff
authors.forename: Celeste D
authors.initials: CD
authors.lastname: Li
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Kelly
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Moura
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Lakshmanan
authors.forename: Joel S
authors.initials: JS
authors.lastname: Freundlich
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Valderramos
authors.forename: Catherine
authors.initials: C
authors.lastname: Vilcheze
authors.forename: Mark
authors.initials: M
authors.lastname: Siedner
authors.forename: Jennifer H-C
authors.initials: JH
authors.lastname: Tsai
authors.forename: Brie
authors.initials: B
authors.lastname: Falkard
authors.forename: Amar Bir Singh
authors.initials: AB
authors.lastname: Sidhu
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Purcell
authors.forename: Paul
authors.initials: P
authors.lastname: Gratraud
authors.forename: Laurent
authors.initials: L
authors.lastname: Kremer
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Waters
authors.forename: Guy
authors.initials: G
authors.lastname: Schiehser
authors.forename: David P
authors.initials: DP
authors.lastname: Jacobus
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Janse
authors.forename: Arba
authors.initials: A
authors.lastname: Ager
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.forename: James C
authors.initials: JC
authors.lastname: Sacchettini
authors.forename: Volker
authors.initials: V
authors.lastname: Heussler
authors.forename: Photini
authors.initials: P
authors.lastname: Sinnis
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D017353:Gene Deletion; D008099:Liver / Q000469:parasitology*; D008288:Malaria / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D016254:Mutagenesis, Insertional; D018512:Parasitemia; D010962:Plasmodium berghei / Q000201:enzymology / Q000254:growth & development / Q000472:pathogenicity*; D010963:Plasmodium falciparum / Q000201:enzymology / Q000254:growth & development / Q000472:pathogenicity*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D014260:Triclosan / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D014260:Triclosan