A novel ABCG-like transporter of Trypanosoma cruzi is
involved in natural resistance to benznidazole |
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Authors: | Bianca Zingales Rafael Gomes Aquino Araujo Margoth Moreno Jaques Franco Pedro Henrique Nascimento Aguiar Solange Lessa Nunes Marcelo Nunes Silva Susan Ienne Carlos Renato Machado Adeilton Brand?o |
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Institution: | 1.Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brasil;2.Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil;3.Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz-Fiocruz, Rio de Janeiro, RJ, Brasil |
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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. |
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