Document Detail


The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites.
MedLine Citation:
PMID:  19064257     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Min Yu; T R Santha Kumar; Louis J Nkrumah; Alida Coppi; Silke Retzlaff; Celeste D Li; Brendan J Kelly; Pedro A Moura; Viswanathan Lakshmanan; Joel S Freundlich; Juan-Carlos Valderramos; Catherine Vilcheze; Mark Siedner; Jennifer H-C Tsai; Brie Falkard; Amar Bir Singh Sidhu; Lisa A Purcell; Paul Gratraud; Laurent Kremer; Andrew P Waters; Guy Schiehser; David P Jacobus; Chris J Janse; Arba Ager; William R Jacobs; James C Sacchettini; Volker Heussler; Photini Sinnis; David A Fidock
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cell host & microbe     Volume:  4     ISSN:  1934-6069     ISO Abbreviation:  Cell Host Microbe     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-12-09     Completed Date:  2009-01-02     Revised Date:  2014-02-24    
Medline Journal Info:
Nlm Unique ID:  101302316     Medline TA:  Cell Host Microbe     Country:  United States    
Other Details:
Languages:  eng     Pagination:  567-78     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antimalarials / pharmacology
Gene Deletion
Liver / parasitology*
Malaria / parasitology
Mice
Mice, Inbred C57BL
Mutagenesis, Insertional
Parasitemia
Plasmodium berghei / enzymology,  growth & development,  pathogenicity*
Plasmodium falciparum / enzymology,  growth & development,  pathogenicity*
Protozoan Proteins / genetics,  metabolism*
Triclosan / pharmacology
Grant Support
ID/Acronym/Agency:
083811//Wellcome Trust; P01 AI060342/AI/NIAID NIH HHS; P01 AI060342-010002/AI/NIAID NIH HHS; P01 AI060342-020002/AI/NIAID NIH HHS; P01 AI060342-030002/AI/NIAID NIH HHS; P01 AI060342-040002/AI/NIAID NIH HHS; P01 AI060342-050002/AI/NIAID NIH HHS; R01 AI056840/AI/NIAID NIH HHS; R01 AI056840-05A2/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Antimalarials; 0/Protozoan Proteins; 4NM5039Y5X/Triclosan
Comments/Corrections
Comment In:
Cell Host Microbe. 2008 Dec 11;4(6):509-11   [PMID:  19064250 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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