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A Novel High-Content Phenotypic Screen To Identify Inhibitors of Mitochondrial DNA Maintenance in Trypanosomes
Migla Miskinyte1, John C Dawson2, Ashraff Makda2
1Institute of Immunology and Infection Research, University of Edinburghgrid.4305.2, Edinburgh, United Kingdom.
Abstract:
Kinetoplastid parasites cause diverse neglected diseases in humans and livestock, with an urgent need for new treatments. The survival of kinetoplastids depends on their uniquely structured mitochondrial genome (kDNA), the eponymous kinetoplast. Here, we report the development of a high-content screen for pharmacologically induced kDNA loss, based on specific staining of parasites and automated image analysis. As proof of concept, we screened a diverse set of ∼14,000 small molecules and exemplify a validated hit as a novel kDNA-targeting compound.
Insights
Researchers developed a new high-content screen to find drugs that cause kinetoplast DNA (kDNA) loss in parasites. This screen identified a novel compound targeting kDNA, offering a potential new treatment for neglected diseases.
Area of Science:
- Parasitology
- Drug Discovery
- Molecular Biology
Background:
- Kinetoplastid parasites cause significant human and livestock diseases.
- Existing treatments are insufficient, highlighting the need for novel therapeutic strategies.
- Kinetoplast DNA (kDNA) is essential for kinetoplastid survival and represents a promising drug target.
Purpose of the Study:
- To develop and validate a high-content screening assay for identifying compounds that induce kDNA loss.
- To discover novel small molecules targeting kDNA in kinetoplastid parasites.
- To provide a new tool for anti-kinetoplastid drug discovery.
Main Methods:
- Development of a high-content screening assay utilizing specific parasite staining.
- Implementation of automated image analysis for quantifying kDNA loss.
- Screening of approximately 14,000 diverse small molecules.
Main Results:
- Successful development of a robust assay for pharmacologically induced kDNA loss.
- Identification of a validated hit compound with novel kDNA-targeting activity.
- Demonstration of the assay's potential for large-scale drug screening.
Conclusions:
- The developed high-content screen is effective for identifying kDNA-targeting compounds.
- The validated hit compound represents a promising starting point for new anti-kinetoplastid drug development.
- This approach offers a valuable platform for discovering treatments for neglected kinetoplastid diseases.
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