title: The methylerythritol phosphate pathway for isoprenoid biosynthesis in coccidia: presence and sensitivity to fosmidomycin.
abstract: 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.
authors.affiliation: EA2106 Biomolécules et Biotechnologies Végétales, UFR Sciences Pharmaceutiques, Université de Tours, 37200 Tours, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Clastre
authors.forename: Armelle
authors.initials: A
authors.lastname: Goubard
authors.forename: Anne
authors.initials: A
authors.lastname: Prel
authors.forename: Zoia
authors.initials: Z
authors.lastname: Mincheva
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Viaud-Massuart
authors.forename: Daniel
authors.initials: D
authors.lastname: Bout
authors.forename: Marc
authors.initials: M
authors.lastname: Rideau
authors.forename: Florence
authors.initials: F
authors.lastname: Velge-Roussel
authors.forename: Fabrice
authors.initials: F
authors.lastname: Laurent
mesh_terms: 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
chemical_list: D006540:Herbicides; D007555:Isoxazoles; D023303:Oxazolidinones; D013729:Terpenes; D005578:Fosfomycin; C095255:clomazone; C024640:fosmidomycin; D004896:Erythritol