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 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
Min
M
Department of Microbiology, Columbia University, New York, NY 10032, USA.
Kumar
T R Santha
TR
Nkrumah
Louis J
LJ
Coppi
Alida
A
Retzlaff
Silke
S
Li
Celeste D
CD
Kelly
Brendan J
BJ
Moura
Pedro A
PA
Lakshmanan
Viswanathan
V
Freundlich
Joel S
JS
Valderramos
Juan-Carlos
JC
Vilcheze
Catherine
C
Siedner
Mark
M
Tsai
Jennifer H-C
JH
Falkard
Brie
B
Sidhu
Amar Bir Singh
AB
Purcell
Lisa A
LA
Gratraud
Paul
P
Kremer
Laurent
L
Waters
Andrew P
AP
Schiehser
Guy
G
Jacobus
David P
DP
Janse
Chris J
CJ
Ager
Arba
A
Jacobs
William R
WR
Sacchettini
James C
JC
Heussler
Volker
V
Sinnis
Photini
P
Fidock
David A
DA
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
D000962:Antimalarials; D015800:Protozoan Proteins; D014260:Triclosan