Image-Based In Vitro Screening Reveals the Trypanostatic Activity of Hydroxymethylnitrofurazone against Trypanosoma cruzi

Hydroxymethylnitrofurazone (NFOH) is a therapeutic candidate for Chagas disease (CD). It has negligible hepatotoxicity in a murine model compared to the front-line drug benznidazole (BZN). Here, using Trypanosoma cruzi strains that express bioluminescent and/or fluorescent reporter proteins, we furt...

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Bibliographic Details
Published in:International journal of molecular sciences 2021-07, Vol.22 (13), p.6930
Main Authors: Scarim, Cauê, Olmo, Francisco, Ferreira, Elizabeth, Chin, Chung, Kelly, John, Francisco, Amanda
Format: Article
Language:English
Subjects:
Animal models
Animal research
Asymptomatic
Benznidazole
Biocompatibility
Bioluminescence
bioluminescence imaging
Chagas disease
Chronic infection
Communication
Cyclophosphamide
Drug dosages
Experimentation
Fluorescence
Genomes
Hepatotoxicity
hydroxymethylnitrofurazone
In vivo methods and tests
Infections
Metabolism
Microscopy
Mutagenesis
Parasites
Protozoa
Trypanosoma cruzi
trypanostatic effect
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Summary:Hydroxymethylnitrofurazone (NFOH) is a therapeutic candidate for Chagas disease (CD). It has negligible hepatotoxicity in a murine model compared to the front-line drug benznidazole (BZN). Here, using Trypanosoma cruzi strains that express bioluminescent and/or fluorescent reporter proteins, we further investigated the in vitro and in vivo activity of NFOH to define whether the compound is trypanocidal or trypanostatic. The in vitro activity was assessed by exploiting the fluorescent reporter strain using wash-out assays and real-time microscopy. For animal experimentation, BALB/c mice were inoculated with the bioluminescent reporter strain and assessed by highly sensitive in vivo and ex vivo imaging. Cyclophosphamide treatment was used to promote parasite relapse in the chronic stage of infection. Our data show that NFOH acts by a trypanostatic mechanism, and that it is more active than BZN in vitro against the infectious trypomastigote form of Trypanosoma cruzi. We also found that it is more effective at curing experimental infections in the chronic stage, compared with the acute stage, a feature that it shares with BZN. Therefore, given its reduced toxicity, enhanced anti-trypomastigote activity, and curative properties, NFOH can be considered as a potential therapeutic option for Chagas disease, perhaps in combination with other trypanocidal agents.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms22136930