Published in
Instituto Oswaldo Cruz, Ministério da Saúde, Memórias do Instituto Oswaldo Cruz., 3(110), p. 433-444
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A novel ABCG-like transporter of Trypanosoma cruzi is involved in natural resistance to benznidazole
,
Araujo,Rafael Gomes Aquino,
Rafael Gomes Aquino Araujo,
Margoth Moreno,
Moreno,Margoth,
Jaques Franco,
Franco,Jaques,
Pedro Henrique Nascimento Aguiar,
Aguiar,Pedro Henrique Nascimento,
Nunes,Solange Lessa,
Silva,Marcelo Nunes,
Marcelo Nunes Silva,
Susan Ienne,
Ienne,Susan
and other authors.
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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.