Transcriptomic analysis from a Benznidazole-resistant clone reveals Nitroreductase I-independent resistance in Trypanosoma cruzi

The enzyme nitroreductase I (NTRI) has been implicated as the primary gene responsible for benznidazole (Bz) and nifurtimox resistance in Trypanosoma cruzi. However, Bz-resistant field T. cruzi parasites with the wild-type NTR-I enzyme suggest that other mechanisms independent of this enzyme could be involved in the resistance phenotype. To investigate these different mechanisms, in this paper, we pressured a Trypanosoma cruzi clone with a high Bz concentration for several generations to select Bz-resistant clones. Surprisingly, we found a highly drug-resistant clone carrying a wild-type NTRI. The RNA-seq analysis showed that genes involved in metabolic pathways related to oxidative stress, energy metabolism, membrane transporters, DNA repair, and protein synthesis were affected. Our results support the idea that resistance to benznidazole is a multigenic trait. Deep knowledge of these genes is essential for the development of new drugs to treat Chagas disease