A Repurposing Approach Identifies Off-Patent Drugs with Fungicidal Cryptococcal Activity, a Common Structural Chemotype, and Pharmacological Properties Relevant to the Treatment of Cryptococcosis
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New, more accessible therapies for cryptococcosis represent an unmet clinical need of global importance. We took a repurposing approach to identify previously developed drugs with fungicidal activity toward Cryptococcus neoformans , using a high-throughput screening assay designed to detect drugs that directly kill fungi. From a set of 1,120 off-patent medications and bioactive molecules, we identified 31 drugs/molecules with fungicidal activity, including 15 drugs for which direct antifungal activity had not previously been reported. A significant portion of the drugs are orally bioavailable and cross the blood-brain barrier, features key to the development of a widely applicable anticryptococcal agent. Structural analysis of this set revealed a common chemotype consisting of a hydrophobic moiety linked to a basic amine, features that are common to drugs that cross the blood-brain barrier and access the phagolysosome, two important niches of C. neoformans . Consistent with their fungicidal activity, the set contains eight drugs that are either additive or synergistic in combination with fluconazole. Importantly, we identified two drugs, amiodarone and thioridazine, with activity against intraphagocytic C. neoformans . Finally, the set of drugs is also enriched for molecules that inhibit calmodulin, and we have confirmed that seven drugs directly bind C. neoformans calmodulin, providing a molecular target that may contribute to the mechanism of antifungal activity. Taken together, these studies provide a foundation for the optimization of the antifungal properties of a set of pharmacologically attractive scaffolds for the development of novel anticryptococcal therapies.
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A screen with the Prestwick Chemical Library of 1,120 off-patent drugs and molecules identified 31 molecules with fungilytic activity.
“For example, a screen with the Prestwick Chemical Library of 1,120 off-patent drugs and molecules identified 31 molecules with fungilytic activity111.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [111]
Analysis of the chemical structures of drugs with anti-cryptococcal activity revealed a general structure comprising a hydrophobic or lipophilic moiety linked to a cationic amine substituent.
“Analysis of the chemical structures of drugs with anti-cryptococcal activity revealed a general structure comprising a hydrophobic or lipophilic moiety linked to a cationic amine substituent111.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [111]
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- Authors
- Butts, A., DiDone, L., Koselny, K., Baxter, B. K., Chabrier-Rosello, Y., Wellington, M., & Krysan, D. J.
- Affiliations
- University of Rochester (US)
- University of Rochester Medicine (US)
- Pediatrics, University of Rochester, Rochester, New York, USA
- Venue
- Eukaryotic Cell
- Publisher
- American Society for Microbiology
- Published
- 2013-02
- Volume
- 12
- Issue
- 2
- Pages
- 278-287
- ISSN
- 1535-9778 (ISSN-L)
- 1535-9786
- PMC
- PMC3571299
- OpenAlex
- W2117206304
- Cited by
- 95
- References
- 46
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 2 · 2023: 13 · 2022: 8 · 2021: 16 · 2020: 8 · 2019: 5 · 2018: 3 · 2017: 6 · 2016: 12 · 2015: 5 · 2014: 6 · 2013: 3
- FWCI
- 3.35
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Locations
- Eukaryotic Cell (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Center, University of Rochester
- National Institute of Allergy and Infectious Diseases (T32AI007464, R01AI091422)
- National Center for Research Resources (KL2RR024136)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- cryptococcosis, Cryptococcus neoformans, drug repurposing, off-patent drugs, fungicidal activity, blood-brain barrier, oral bioavailability, chemotypes, amiodarone, thioridazine, calmodulin inhibition, fluconazole synergy, phagolysosomes, antifungal drug discovery
- MeSH terms
- Adenylate Kinase, Amiodarone, Animals, Antifungal Agents, Calmodulin, Cells, Cultured, Cryptococcosis, Cryptococcus neoformans, Drug Synergism, Fungal Proteins, Humans, Microbial Sensitivity Tests, Patents as Topic, Phagocytes, Structure-Activity Relationship, Suloctidil, Thioridazine, Fluconazole, Mice, Small Molecule Libraries, High-Throughput Screening Assays, Hydrophobic and Hydrophilic Interactions
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