title: A novel ABCG-like transporter of Trypanosoma cruzi is involved in natural resistance to benznidazole.
abstract: Benznidazole (BZ) is one of the two drugs used for Chagas disease treatment. Nevertheless therapeutic failures of BZ have been reported, which were mostly attributed to variable drug susceptibility among Trypanosoma cruzi strains. ATP-binding cassette (ABC) transporters are involved in a variety of translocation processes and some members have been implicated in drug resistance. Here we report the characterisation of the first T. cruzi ABCG transporter gene, named TcABCG1, which is over-expressed in parasite strains naturally resistant to BZ. Comparison of TcABCG1 gene sequence of two TcI BZ-resistant strains with CL Brener BZ-susceptible strain showed several single nucleotide polymorphisms, which determined 11 amino acid changes. CL Brener transfected with TcI transporter genes showed 40-47% increased resistance to BZ, whereas no statistical significant increment in drug resistance was observed when CL Brener was transfected with the homologous gene. Only in the parasites transfected with TcI genes there was 2-2.6-fold increased abundance of TcABCG1 transporter protein. The analysis in wild type strains also suggests that the level of TcABCG1 transporter is related to BZ natural resistance. The characteristics of untranslated regions of TcABCG1 genes of BZ-susceptible and resistant strains were investigated by computational tools.
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: Bianca
authors.initials: B
authors.lastname: Zingales
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: Rafael Gomes Aquino
authors.initials: RG
authors.lastname: Araujo
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: Margoth
authors.initials: M
authors.lastname: Moreno
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: Jaques
authors.initials: J
authors.lastname: Franco
authors.affiliation: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil.
authors.forename: Pedro Henrique Nascimento
authors.initials: PH
authors.lastname: Aguiar
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: Solange Lessa
authors.initials: SL
authors.lastname: Nunes
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: Marcelo Nunes
authors.initials: MN
authors.lastname: Silva
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brasil.
authors.forename: Susan
authors.initials: S
authors.lastname: Ienne
authors.affiliation: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil.
authors.forename: Carlos Renato
authors.initials: CR
authors.lastname: Machado
authors.affiliation: Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz-Fiocruz, Rio de Janeiro, RJ, Brasil.
authors.forename: Adeilton
authors.initials: A
authors.lastname: Brandão
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D016054:DNA, Protozoan / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D005838:Genotype; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics; D009593:Nitroimidazoles / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D010802:Phylogeny; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000235:genetics*
chemical_list: D018528:ATP-Binding Cassette Transporters; D016054:DNA, Protozoan; D026901:Membrane Transport Proteins; D009593:Nitroimidazoles; D014344:Trypanocidal Agents; C009999:benzonidazole