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

• Published in: Memórias do Instituto Oswaldo Cruz Vol. 110; no. 3; pp. 433 - 444
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Brazil Fundação Oswaldo Cruz, Fiocruz 01-05-2015; Instituto Oswaldo Cruz, Ministério da Saúde; Fundação Oswaldo Cruz (FIOCRUZ)
• Subjects: ABCG transporter; Animals; ATP-Binding Cassette Transporters - genetics; benznidazole resistance; Chagas disease; DNA, Protozoan - genetics; Drug Resistance - genetics; Genotype; Humans; Membrane Transport Proteins - genetics; Nitroimidazoles - pharmacology; Parasitic Sensitivity Tests; PARASITOLOGY; Phylogeny; single nucleotide polymorphisms; strains; T. cruzi; T. cruzi strains; transcript abundance; TROPICAL MEDICINE; Trypanocidal Agents - pharmacology; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - genetics; Chagas disease; ABCG transporter; T. cruzi; strains; single nucleotide polymorphisms; benznidazole resistance; transcript abundance
• ISSN: 1678-8060; 0074-0276; 1678-8060
• DOI: 10.1590/0074-02760140407

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.