Mapping benznidazole resistance in trypanosomatids and exploring evolutionary histories of nitroreductases and ABCG transporter protein sequences

Autor(es)

Petravicius, Pamela O. ^[1] ; Costa-Martins, Andre G. ^[2] ; Silva, Marcelo N. ^[1] ; Reis-Cunha, Joao L. ^[3] ; Bartholomeu, Daniella C. ^[3] ; Teixeira, Marta M. G. ^[2] ; Zingales, Bianca ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Quim, Dept Bioquim, Av Prof Lineu Prestes 748, BR-05508000 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Inst Ciencias Biomed, Dept Parasitol, Av Prof Lineu Prestes 1374, BR-05508900 Sao Paulo, SP - Brazil

^[3] Univ Fed Minas Gerais, Dept Parasitol, Av Antonio Carlos 6627, BR-31270901 Belo Horizonte, MG - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Acta Tropica; v. 200, DEC 2019.
• Citações Web of Science: 0

Resumo

The nitro-heterocyclic compound benznidazole (BZ) is the first-line drug for the treatment of Chagas disease, caused by the protozoan Trypanosoma cruzi. However, therapeutic failures are common for reasons that include the influences of parasite and host genetics, the effects of toxicity on adherence to treatment, and difficulties in demonstrating parasitological cure. To obtain information on the origin of the resistance to BZ and eliminate from the scenery the participation of the host, initially we mapped the susceptibility to the drug in thirteen species of seven genera of the family Trypanosomatidae. We verified that all Trypanosoma species are sensitive to low concentrations of the drug (IC50 2.7 to 25 mu M) while Non-Trypanosoma species are highly resistant to these concentrations. The two groups of parasites correspond to the major phylogenetic lineages of trypanosomatids. Next, we searched in the trypanosomatid genome databases homologs of two type-I nitroreductases (NTR-1 and OYE) and an ABC transporter (ABCG1) that have been associated with BZ resistance in T. cruzi. The predicted proteins were characterized regarding domains and used for phylogenetic analyses. Homologous NTR-1 genes were found in all trypanosomatids investigated and the structural characteristics of the enzyme suggest that it may be functional. OYE genes were absent in BZ-sensitive African trypanosomes, which excludes the participation of this enzyme in BZ bio-activation. Two copies of ABCG1 genes were observed in most BZ resistant species, while Trypanosoma species exhibit only one copy per haploid genome. Functional studies are required to verify the involvement of these genes in BZ resistance. In addition, since multiple mechanisms can contribute to BZ susceptibility, our study poses a range of organisms highly resistant to BZ in which these aspects can be investigated. Preliminary studies on BZ uptake indicate marked differences between BZ-sensitive and BZ-resistant species. (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
• Modalidade de apoio: Auxílio à Pesquisa - Regular