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

Abstract

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.

Transcriptome and Functional Genomics Reveal the Participation of Adenine Phosphoribosyltransferase in Trypanosoma cruzi Resistance to Benznidazole

“…This suggests that cyclophilin plays an important biological role in resistance to Bz [Rego et al, ]. Other genes implicated in transport, such as hexose transporters [Murta et al, ] and ABC transporters [Zingales et al, ], have been linked to resistance in T. cruzi ; consistent with our results, these have also been found to be up‐regulated. These transporters lead to drug resistance by increasing drug efflux from the cell, thus decreasing the effective intracellular drug concentration [Sauvage et al, ].…”

Quantitative Laser Biospeckle Method for the Evaluation of the Activity of Trypanosoma cruzi Using VDRL Plates and Digital Analysis

“…cruzi has a TcABCG1 transporter protein, located on the plasma membrane for which a nucleotide binding, a membrane and a transmembrane domain have been described. This protein is involved in a variety of translocation processes including benznidazole [20]. Transport processes are rapid and efficient mechanisms and could respond to intracellular and extracellular signals [21].…”

New 1,2,3‐triazole‐based analogues of benznidazole for use against Trypanosoma cruzi infection: In vitro and in vivo evaluations

“…In addition to being genotoxic, this drug can also cause muscle pain, joint pain, paraesthesia, cutaneous hypersensitivity with the appearance of rash, generalized oedema, thrombocytopenia, fever, lymphadenopathy, purpura and agranulocytosis, peripheral neuropathy and polyneuropathy . In addition, Bnz is ineffective in treating some naturally resistant strains, which is concerning to healthcare organizations . Therefore, the search for new analogues of this drug could be important in the treatment of the CD.…”

“…[12] In addition, Bnz is ineffective in treating some naturally resistant strains, which is concerning to healthcare organizations. [13] Therefore, the search for new analogues of this drug could be important in the treatment of the CD.…”