The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites.
Min Yu
(1)
,
T R Santha Kumar
,
Louis J Nkrumah
,
Alida Coppi
,
Silke Retzlaff
,
Celeste D Li
(2, 3, 4)
,
Brendan J Kelly
,
Pedro A Moura
,
Viswanathan Lakshmanan
,
Joel S Freundlich
,
Juan-Carlos Valderramos
,
Catherine Vilcheze
,
Mark Siedner
,
Jennifer H-C Tsai
(5)
,
Brie Falkard
,
Amar Bir Singh Sidhu
(6, 7, 8)
,
Lisa A Purcell
,
Paul Gratraud
(9)
,
Laurent Kremer
(9)
,
Andrew P Waters
(10)
,
Guy Schiehser
,
David P Jacobus
,
Chris J Janse
(10)
,
Arba Ager
,
William R Jacobs
(11)
,
James C Sacchettini
,
Volker Heussler
,
Photini Sinnis
,
David A Fidock
1
UCFV -
University College of the Fraser Valley
2 CIMS - Courant Institute of Mathematical Sciences [New York]
3 IVPP - Institute of Vertebrate Paleontology and Paleoanthropology
4 IEM - Institut Européen des membranes
5 Department of Biochemistry and Biophysics
6 Laboratory of Molecular Neurochemistry
7 Laboratory of Molecular Neurochemistry, Department of Pediatrics
8 INAF - Institut de Neurobiologie Alfred Fessard
9 DIMNP - Dynamique des interactions membranaires normales et pathologiques
10 Dpt of Parasitology [Leiden]
11 HHMI - Howard Hughes Medical Institute
2 CIMS - Courant Institute of Mathematical Sciences [New York]
3 IVPP - Institute of Vertebrate Paleontology and Paleoanthropology
4 IEM - Institut Européen des membranes
5 Department of Biochemistry and Biophysics
6 Laboratory of Molecular Neurochemistry
7 Laboratory of Molecular Neurochemistry, Department of Pediatrics
8 INAF - Institut de Neurobiologie Alfred Fessard
9 DIMNP - Dynamique des interactions membranaires normales et pathologiques
10 Dpt of Parasitology [Leiden]
11 HHMI - Howard Hughes Medical Institute
T R Santha Kumar
- Fonction : Auteur
Louis J Nkrumah
- Fonction : Auteur
Alida Coppi
- Fonction : Auteur
Silke Retzlaff
- Fonction : Auteur
Brendan J Kelly
- Fonction : Auteur
Pedro A Moura
- Fonction : Auteur
Viswanathan Lakshmanan
- Fonction : Auteur
Joel S Freundlich
- Fonction : Auteur
Juan-Carlos Valderramos
- Fonction : Auteur
Catherine Vilcheze
- Fonction : Auteur
Mark Siedner
- Fonction : Auteur
Brie Falkard
- Fonction : Auteur
Lisa A Purcell
- Fonction : Auteur
Laurent Kremer
- Fonction : Auteur
- PersonId : 181434
- IdHAL : laurent-kremer
- ORCID : 0000-0002-6604-4458
- IdRef : 121427218
Guy Schiehser
- Fonction : Auteur
David P Jacobus
- Fonction : Auteur
Arba Ager
- Fonction : Auteur
James C Sacchettini
- Fonction : Auteur
Volker Heussler
- Fonction : Auteur
Photini Sinnis
- Fonction : Auteur
David A Fidock
- Fonction : Auteur
Résumé
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.