ArticlePLoS neglected tropical diseases2020
Non-invasive monitoring of drug action: A new live in vitro assay design for Chagas' disease drug discovery.
Article in PLoS neglected tropical diseases, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 13 citations in OpenAlex.
- Population pharmacokinetic-pharmacodynamic analysis of benznidazole monotherapy and combination therapy with fosravuconazole in chronic Chagas disease (BENDITA).PLoS neglected tropical diseases · 2025Trial
- Induced pluripotent stem cell-derived human macrophages as an infection model for Trypanosoma cruzi.PLoS neglected tropical diseases · 2025Article
- Pharmacokinetic-pharmacodynamic modeling of benznidazole and its antitrypanosomal activity in a murine model of chronic Chagas disease.PLoS neglected tropical diseases · 2025Article
- Reporter genes and transgenicFrontiers in medicine · 2025Review
- Article
- Past and future of trypanosomatids high-throughput phenotypic screening.Memorias do Instituto Oswaldo Cruz · 2022Article
- Paving the Way: Contributions of Big Data to Apicomplexan and Kinetoplastid Research.Frontiers in cellular and infection microbiology · 2022Review
- Live-imaging rate-of-kill compound profiling for Chagas disease drug discovery with a new automated high-content assay.PLoS neglected tropical diseases · 2021Article
- Combination With Tomatidine Improves the Potency of Posaconazole AgainstFrontiers in cellular and infection microbiology · 2021Article
- Biospektrum : Zeitschrift der Gesellschaft fur Biologishe Chemie (GBCH) und der Vereinigung fur Allgemeine und Angewandte Mikrobiologie (VAAM) · 2021Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
New assay designs are needed to improve the predictive value of the Trypanosoma cruzi in vitro tests used as part of the Chagas' disease drug development pipeline. Here, we employed a green fluorescent protein (eGFP)-expressing parasite line and live high-content imaging to monitor the growth of T. cruzi amastigotes in mouse embryonic fibroblasts. A novel assay design allowed us to follow parasite numbers over 6 days, in four-hour intervals, while occupying the microscope for only 24 hours per biological replicate. Dose-response curves were calculated for each time point after addition of test compounds, revealing how EC50 values first decreased over the time of drug exposure, and then leveled off. However, we observed that parasite numbers could vary, even in the untreated controls, and at different sites in the same well, which caused variability in the EC50 values. To overcome this, we established that fold change in parasite number per hour is a more robust and informative measure of drug activity. This was calculated based on an exponential growth model for every biological sample. The net fold change per hour is the result of parasite replication, differentiation, and death. The calculation of this fold change enabled us to determine the tipping point of drug action, i.e. the time point when the death rate of the parasites exceeded the growth rate and the fold change dropped below 1, depending on the drug concentration and exposure time. This revealed specific pharmacodynamic profiles of the benchmark drugs benznidazole and posaconazole.
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