Zingales Bianca, Araujo Rafael Gomes Aquino, Moreno Margoth, Franco Jaques, Aguiar Pedro Henrique Nascimento, Nunes Solange Lessa, Silva Marcelo Nunes, Ienne Susan, Machado Carlos Renato, Brandão Adeilton
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brasil.
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil.
Mem Inst Oswaldo Cruz. 2015 May;110(3):433-44. doi: 10.1590/0074-02760140407. Epub 2015 Apr 28.
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.
苯硝唑（BZ）是用于治疗恰加斯病的两种药物之一。然而，已有BZ治疗失败的报道，这主要归因于克氏锥虫菌株之间不同的药物敏感性。ATP结合盒（ABC）转运蛋白参与多种转运过程，一些成员与耐药性有关。在此，我们报告了首个克氏锥虫ABCG转运蛋白基因的特征，该基因名为TcABCG1，在对BZ天然耐药的寄生虫菌株中过度表达。将两个TcI BZ耐药菌株的TcABCG1基因序列与CL Brener BZ敏感菌株进行比较，发现了几个单核苷酸多态性，这些多态性导致了11个氨基酸的变化。用TcI转运蛋白基因转染的CL Brener对BZ的耐药性增加了40 - 47%，而当用同源基因转染CL Brener时，未观察到耐药性有统计学意义的增加。仅在用TcI基因转染的寄生虫中，TcABCG1转运蛋白的丰度增加了2 - 2.6倍。对野生型菌株的分析也表明，TcABCG1转运蛋白的水平与BZ天然耐药性有关。通过计算工具研究了BZ敏感和耐药菌株的TcABCG1基因非翻译区的特征。
