Transcriptomic analysis of benznidazole-resistant Trypanosoma cruzi clone reveals nitroreductase I-independent resistance mechanisms.
The enzyme nitroreductase I (NTRI) has been implicated as the primary gene responsible for resistance to benznidazole (Bz) and nifurtimox in Trypanosoma cruzi. However, Bz-resistant T. cruzi field isolates carrying the wild-type NTR-I enzyme suggest that additional mechanisms independent of this enz...
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Public Library of Science (PLoS)
2025-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0314189 |
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| author | Ana María Mejía-Jaramillo Hader Ospina-Zapata Geysson Javier Fernandez Omar Triana-Chávez |
| author_facet | Ana María Mejía-Jaramillo Hader Ospina-Zapata Geysson Javier Fernandez Omar Triana-Chávez |
| author_sort | Ana María Mejía-Jaramillo |
| collection | DOAJ |
| description | The enzyme nitroreductase I (NTRI) has been implicated as the primary gene responsible for resistance to benznidazole (Bz) and nifurtimox in Trypanosoma cruzi. However, Bz-resistant T. cruzi field isolates carrying the wild-type NTR-I enzyme suggest that additional mechanisms independent of this enzyme may contribute to the resistance phenotype. To investigate these alternative mechanisms, in this paper, we pressured a Trypanosoma cruzi clone with a high Bz concentration over several generations to select Bz-resistant clones. Surprisingly, we found a highly drug-resistant clone carrying a wild-type NTRI. However, the knockout of this gene using CRISPR-Cas9 in the sensitive clone showed that NTRI indeed induces resistance to Bz and supports the idea that the resistant one exhibits mechanisms other than NTRI. To explore these new mechanisms, we performed an RNA-seq analysis, which revealed genes involved in metabolic pathways related to oxidative stress, energy metabolism, membrane transporters, DNA repair, and protein synthesis. Our results support the idea that resistance to benznidazole is a multigenic trait. A Deeper understanding of these genes is essential for developing new drugs to treat Chagas disease. |
| format | Article |
| id | doaj-art-61ad38f3928a4e159401db5b5edcfcbe |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-61ad38f3928a4e159401db5b5edcfcbe2025-08-20T03:32:40ZengPublic Library of Science (PLoS)PLoS ONE1932-62032025-01-01202e031418910.1371/journal.pone.0314189Transcriptomic analysis of benznidazole-resistant Trypanosoma cruzi clone reveals nitroreductase I-independent resistance mechanisms.Ana María Mejía-JaramilloHader Ospina-ZapataGeysson Javier FernandezOmar Triana-ChávezThe enzyme nitroreductase I (NTRI) has been implicated as the primary gene responsible for resistance to benznidazole (Bz) and nifurtimox in Trypanosoma cruzi. However, Bz-resistant T. cruzi field isolates carrying the wild-type NTR-I enzyme suggest that additional mechanisms independent of this enzyme may contribute to the resistance phenotype. To investigate these alternative mechanisms, in this paper, we pressured a Trypanosoma cruzi clone with a high Bz concentration over several generations to select Bz-resistant clones. Surprisingly, we found a highly drug-resistant clone carrying a wild-type NTRI. However, the knockout of this gene using CRISPR-Cas9 in the sensitive clone showed that NTRI indeed induces resistance to Bz and supports the idea that the resistant one exhibits mechanisms other than NTRI. To explore these new mechanisms, we performed an RNA-seq analysis, which revealed genes involved in metabolic pathways related to oxidative stress, energy metabolism, membrane transporters, DNA repair, and protein synthesis. Our results support the idea that resistance to benznidazole is a multigenic trait. A Deeper understanding of these genes is essential for developing new drugs to treat Chagas disease.https://doi.org/10.1371/journal.pone.0314189 |
| spellingShingle | Ana María Mejía-Jaramillo Hader Ospina-Zapata Geysson Javier Fernandez Omar Triana-Chávez Transcriptomic analysis of benznidazole-resistant Trypanosoma cruzi clone reveals nitroreductase I-independent resistance mechanisms. PLoS ONE |
| title | Transcriptomic analysis of benznidazole-resistant Trypanosoma cruzi clone reveals nitroreductase I-independent resistance mechanisms. |
| title_full | Transcriptomic analysis of benznidazole-resistant Trypanosoma cruzi clone reveals nitroreductase I-independent resistance mechanisms. |
| title_fullStr | Transcriptomic analysis of benznidazole-resistant Trypanosoma cruzi clone reveals nitroreductase I-independent resistance mechanisms. |
| title_full_unstemmed | Transcriptomic analysis of benznidazole-resistant Trypanosoma cruzi clone reveals nitroreductase I-independent resistance mechanisms. |
| title_short | Transcriptomic analysis of benznidazole-resistant Trypanosoma cruzi clone reveals nitroreductase I-independent resistance mechanisms. |
| title_sort | transcriptomic analysis of benznidazole resistant trypanosoma cruzi clone reveals nitroreductase i independent resistance mechanisms |
| url | https://doi.org/10.1371/journal.pone.0314189 |
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