A novel ABCG-like transporter of Trypanosoma cruzi is involved in natural resistance to benznidazole

Autor(es)

Zingales, Bianca ^[1] ; Aquino Araujo, Rafael Gomes ^[1] ; Moreno, Margoth ^[1] ; Franco, Jaques ^[1] ; Nascimento Aguiar, Pedro Henrique ^[2] ; Nunes, Solange Lessa ^[1] ; Silva, Marcelo Nunes ^[1] ; Ienne, Susan ^[1] ; Machado, Carlos Renato ^[2] ; Brandao, Adeilton ^[3]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Quim, Dept Bioquim, Sao Paulo, SP - Brazil

^[2] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Bioquim & Imunol, Belo Horizonte, MG - Brazil

^[3] Fiocruz MS, Inst Oswaldo Cruz, Lab Interdisciplinar Pesquisas Med, BR-21045900 Rio De Janeiro, RJ - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Memórias do Instituto Oswaldo Cruz; v. 110, n. 3, p. 433-444, MAY 2015.
• Citações Web of Science: 17

Resumo

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. (AU)

• Processo FAPESP: 13/13333-8 - Quimioterapia para a Doença de Chagas: falhas terapêuticas para benznidazol e busca de candidatos para alternativas de tratamento
• Beneficiário: Bianca Silvana Zingales
• Linha de fomento: Auxílio à Pesquisa - Regular