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Araújo RGA. ABC transporter and benznidazole resistance in Trypanosoma cruzi. [Masters thesis (Parasitology)]. São Paulo: Instituto de Ciências Biomédicas da Universidade de São Paulo; 2011. Benznidazole (BZ) and Nifurtimox (NFX) are the only available drugs for the treatment of Chagas disease, caused by the protozoan Trypanosoma cruzi. Clinical trials indicate regional differences in the treatment outcome, attributed in part to differences in the drug susceptibility of T. cruzi strains. Several ABC (ATP binding cassette) transporters play an important role in drug resistance. Evidence obtained by our group indicates that a T. cruzi ABC transporter, TcABCG1, is overexpressed in BZ-resistant strains. Thus, the overall goal of our project was to obtain additional evidence for the involvement of TcABCG1 in BZ resistance. The specific goals of the study were: (i) to verify the activity of ABC transporter inhibitors in BZ resistance; (ii) to assess whether the overexpression of the TcABCG1 gene alters the susceptibility to BZ in a BZ-susceptible strain; (iii) to determine the number of TcABCG1 gene copies in some T. cruzi strains; (iv) to characterize the ABC transporter genes in CL Brener genome. After determining the IC50 to BZ in six strains and their classification into susceptible (S) and resistant (R), the effect of three inhibitors of eukaryotic ABC transporters was investigated. Only verapamil increased BZ susceptibility in all the strains. The TcABCG1 gene of Berenice 62 (S), VL10 (R), Silvio (R) and YuYu (R) strains was cloned and sequenced. We transfected in CL Brener (S) TcABCG1 genes of VL10, YuYu and Silvio strains, considered BZ-resistant. The genes were cloned into the pROCKNeo vector. In cultures transfected with Silvio and YuYu genes, an increased BZ resistance of 26 and 32%, respectively, was observed. In cultures transfected with the VL10 and CL Brener genes, the increase in drug resistance was approximately 10%. In the transfected cultures resistance to NFX was also increased. The relative TcABCG1 transcript abundance was determined by real time RT-PCR. In cultures transfected with the CL Brener, Silvio and YuYu gene the increase of transcript abundance was 2.70-; 2.85; and 2.67-fold, respectively. In cultures transfected with the VL10 gene and with the empty vector the transcript abundance increased 1.12and 0.80-fold, respectively. No differences in the TcABCG1 gene copy number in naturally BZsusceptible and resistant strains were observed. The evidence obtained in this study support the hypothesis that TcABCG1 transporter is one of the elements involved in the BZ (and NFX) resistance phenotype. By using bioinformatics tools, we identified 58 hypothetical ABC transporters in CL Brener genome, 36 of which have an annotated allele. The genes are distributed in 16 of the 41 chromosomes. ABC orthologous genes to those of T. cruzi were identified in African trypanosomes and Leishmania spp. Data regarding the phylogenetic analysis and classification of T. cruzi ABC transporters in eight subfamilies (A-H) of eukaryote ABC proteins are presented.

Transportador ABC e resistência a benznidazol em Trypanosoma cruzi.