title: Sulfadiazine resistance in Toxoplasma gondii: no involvement of overexpression or polymorphisms in genes of therapeutic targets and ABC transporters.
abstract: Several treatment failures have been reported for the treatment of toxoplasmic encephalitis, chorioretinitis, and congenital toxoplasmosis. Recently we found three Toxoplasma gondii strains naturally resistant to sulfadiazine and we developed in vitro two sulfadiazine resistant strains, RH-R(SDZ) and ME-49-R(SDZ), by gradual pressure. In Plasmodium, common mechanisms of drug resistance involve, among others, mutations and/or amplification within genes encoding the therapeutic targets dhps and dhfr and/or the ABC transporter genes family. To identify genotypic and/or phenotypic markers of resistance in T. gondii, we sequenced and analyzed the expression levels of therapeutic targets dhps and dhfr, three ABC genes, two Pgp, TgABC.B1 and TgABC.B2, and one MRP, TgABC.C1, on sensitive strains compared to sulfadiazine resistant strains. Neither polymorphism nor overexpression was identified. Contrary to Plasmodium, in which mutations and/or overexpression within gene targets and ABC transporters are involved in antimalarial resistance, T. gondii sulfadiazine resistance is not related to these toxoplasmic genes studied.
authors.affiliation: Laboratoire de Parasitologie-Mycologie, EA 3800, SFR CAP-Santé FED 4231, UFR Médecine, Université de Reims Champagne-Ardenne, 51 rue Cognacq-Jay, 51095 Reims Cedex, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Doliwa
authors.forename: Sandie
authors.initials: S
authors.lastname: Escotte-Binet
authors.forename: Dominique
authors.initials: D
authors.lastname: Aubert
authors.forename: Virginie
authors.initials: V
authors.lastname: Sauvage
authors.forename: Frédéric
authors.initials: F
authors.lastname: Velard
authors.forename: Aline
authors.initials: A
authors.lastname: Schmid
authors.forename: Isabelle
authors.initials: I
authors.lastname: Villena
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D001483:Base Sequence; D002522:Chlorocebus aethiops; D004094:Dihydropteroate Synthase / Q000037:antagonists & inhibitors; D004351:Drug Resistance / Q000235:genetics; D005786:Gene Expression Regulation; D005838:Genotype; D008969:Molecular Sequence Data; D010641:Phenotype; D011110:Polymorphism, Genetic; D013411:Sulfadiazine / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects; D014122:Toxoplasma / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D014709:Vero Cells
chemical_list: D018528:ATP-Binding Cassette Transporters; D000981:Antiprotozoal Agents; D013411:Sulfadiazine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase