Authors

Discussion

Benznidazole and nifurtimox are the front-line drugs used to treat Trypanosoma cruzi infections. The resistance of T. cruzi to these drugs has been reported as one of the leading causes of treatment failure against Chagas disease. However, most of the mechanisms of such resistance remain unknown. Several studies have shown mutagenic and genotoxic effects of Bz, double-stranded breaks in treated parasites possibly caused by nucleotide oxidation and cell cycle arrest, mainly in G0/G1. Other studies have proposed that the mechanism of action of Bz is related to the induction of oxidative stress caused by reactive oxygen species (ROS).

L-threonine 3-dehydrogenase (TDH) plays an essential role in L-threonine catabolism. It catalyzes the NAD(P)+-dependent oxidation of L-threonine to 2-amino-3-oxobutyrate, which is a precursor in the production of glycine and acetyl-coenzyme A. Interestingly, this enzyme was found overexpressed in Bz resistant T. cruzi parasites. However, more is needed to know about its role in this process. For this, TDH was overexpressed in Bz-sensitive parasites, and their response to Bz, oxidative stress, and genetic damage was evaluated. Moreover, some biological features, such as in vitro growth, mitochondrial membrane potential, and cell infectivity, were also estimated. Our results showed that TDH-overexpressing parasites did not have changes in their growth, but they were more resistant to Bz and H₂O₂, and their cellular infectivity increased compared to the control. We found no alterations in the mitochondrial membrane potential or cell cycle in these parasites after Bz treatment. Finally, we submitted the overexpressing TDH parasites to the effect of the MMS compound, an alkylating agent, and gamma radiation that causes the breaking of double-stranded DNA; we found that these parasites were also resistant to genetic damage. Although no previous information relates to TDH with Bz resistance, we propose that TDH has a protective effect on oxidative stress, genetic damage caused by Bz, and the impact of compounds such as H₂O₂, MMS, and gamma radiation in T. cruzi.