The methylerythritol phosphate pathway for isoprenoid biosynthesis in coccidia: presence and sensitivity to fosmidomycin.
The apicoplast is a recently discovered, plastid-like organelle present in most apicomplexa. The methylerythritol phosphate (MEP) pathway involved in isoprenoid biosynthesis is one of the metabolic pathways associated with the apicoplast, and is a new promising therapeutic target in Plasmodium falciparum. Here, we check the presence of isoprenoid genes in four coccidian parasites according to genome database searches. Cryptosporidium parvum and C. hominis, which have no plastid genome, lack the MEP pathway. In contrast, gene expression studies suggest that this metabolic pathway is present in several development stages of Eimeria tenella and in tachyzoites of Toxoplasma gondii. We studied the potential of fosmidomycin, an antimalarial drug blocking the MEP pathway, to inhibit E. tenella and T. gondii growth in vitro. The drug was poorly effective even at high concentrations. Thus, both fosmidomycin sensitivity and isoprenoid metabolism differs substantially between apicomplexan species.
Clastre
Marc
M
EA2106 Biomolécules et Biotechnologies Végétales, UFR Sciences Pharmaceutiques, Université de Tours, 37200 Tours, France.
Goubard
Armelle
A
Prel
Anne
A
Mincheva
Zoia
Z
Viaud-Massuart
Marie-Claude
MC
Bout
Daniel
D
Rideau
Marc
M
Velge-Roussel
Florence
F
Laurent
Fabrice
F
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002645:Chickens; D003044:Coccidia / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D003458:Cryptosporidium / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D016785:Cryptosporidium parvum / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D016786:Eimeria tenella / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D004896:Erythritol / Q000235:genetics / Q000378:metabolism*; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D018503:Genome, Protozoan; D006540:Herbicides / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D051379:Mice; D008808:Mice, Inbred CBA; D023303:Oxazolidinones / Q000494:pharmacology; D013729:Terpenes / Q000378:metabolism*; D014122:Toxoplasma / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism
D006540:Herbicides; D007555:Isoxazoles; D023303:Oxazolidinones; D013729:Terpenes; D005578:Fosfomycin; C095255:clomazone; C024640:fosmidomycin; D004896:Erythritol