ArticleScientific reports2017
Genome-wide mutagenesis and multi-drug resistance in American trypanosomes induced by the front-line drug benznidazole.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 59 citations in OpenAlex.
- Identification of new Trypanosoma cruzi-specific protein synthesis inhibitors by using a developed high-throughput in vitro translation assay.International journal for parasitology. Drugs and drug resistance · 2026Article
- Multitarget Therapeutic Strategies for Chagas Disease: Natural Compounds, Antimicrobial Peptides, and Cell-Based Immunomodulation.Infectious disease reports · 2026Review
- A strategic discovery roadmap towards high-quality leads and drug development candidates for kinetoplastid diseases. Part 3: from lead towards a drug development candidate.The Journal of antimicrobial chemotherapy · 2026Review
- Overcoming Trypanosoma cruzi persistence with a mechanistically distinct drug combination.npj antimicrobials and resistance · 2026Article
- System-based insights into parasitological and clinical treatment failure in Chagas disease.mSystems · 2025Review
- Article
- Hybrid-Capture Target Enrichment in Human Pathogens: Identification, Evolution, Biosurveillance, and Genomic Epidemiology.Pathogens (Basel, Switzerland) · 2024Review
- Discovery of an orally active nitrothiophene-based antitrypanosomal agent.European journal of medicinal chemistry · 2024Article
- Fifteen Years after the Definition ofLife (Basel, Switzerland) · 2023Review
- Benznidazole treatment leads to DNA damage in Trypanosoma cruzi and the persistence of rare widely dispersed non-replicative amastigotes in mice.PLoS pathogens · 2023Article
- Targeting trypanosomes: how chemogenomics and artificial intelligence can guide drug discovery.Biochemical Society transactions · 2023Review
- Impact of Laboratory-Adapted IntracellularMicroorganisms · 2023Article
- Genomic surveillance: a potential shortcut for effective Chagas disease management.Memorias do Instituto Oswaldo Cruz · 2023Article
- Molecular Characterization of Four Mexican Isolates of Trypanosoma cruzi and Their Profile Susceptibility to Nifurtimox.Acta parasitologica · 2022Article
- Laboratory Selection of Trypanosomatid Pathogens for Drug Resistance.Pharmaceuticals (Basel, Switzerland) · 2022Review
- The repositioned drugs disulfiram/diethyldithiocarbamate combined to benznidazole: Searching for Chagas disease selective therapy, preventing toxicity and drug resistance.Frontiers in cellular and infection microbiology · 2022Article
- Drug Target Validation of the Protein KinaseMicrobiology spectrum · 2021Article
- Image-Based In Vitro Screening Reveals the Trypanostatic Activity of Hydroxymethylnitrofurazone againstInternational journal of molecular sciences · 2021Article
- Multidrug resistance protein structure ofVeterinary world · 2021Article
- Repurposing Carvedilol as a Novel Inhibitor of theFrontiers in cellular and infection microbiology · 2021Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects 5-8 million people in Latin America. Although the nitroheterocyclic compound benznidazole has been the front-line drug for several decades, treatment failures are common. Benznidazole is a pro-drug and is bio-activated within the parasite by the mitochondrial nitroreductase TcNTR-1, leading to the generation of reactive metabolites that have trypanocidal activity. To better assess drug action and resistance, we sequenced the genomes of T. cruzi Y strain (35.5 Mb) and three benznidazole-resistant clones derived from a single drug-selected population. This revealed the genome-wide accumulation of mutations in the resistant parasites, in addition to variations in DNA copy-number. We observed mutations in DNA repair genes, linked with increased susceptibility to DNA alkylating and inter-strand cross-linking agents. Stop-codon-generating mutations in TcNTR-1 were associated with cross-resistance to other nitroheterocyclic drugs. Unexpectedly, the clones were also highly resistant to the ergosterol biosynthesis inhibitor posaconazole, a drug proposed for use against T. cruzi infections, in combination with benznidazole. Our findings therefore identify the highly mutagenic activity of benznidazole metabolites in T. cruzi, demonstrate that this can result in multi-drug resistance, and indicate that vigilance will be required if benznidazole is used in combination therapy.
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