title: A repurposing approach identifies off-patent drugs with fungicidal cryptococcal activity, a common structural chemotype, and pharmacological properties relevant to the treatment of cryptococcosis.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Rochester, Rochester, New York, USA.
authors.forename: Arielle
authors.initials: A
authors.lastname: Butts
authors.forename: Louis
authors.initials: L
authors.lastname: DiDone
authors.forename: Kristy
authors.initials: K
authors.lastname: Koselny
authors.forename: Bonnie K
authors.initials: BK
authors.lastname: Baxter
authors.forename: Yeissa
authors.initials: Y
authors.lastname: Chabrier-Rosello
authors.forename: Melanie
authors.initials: M
authors.lastname: Wellington
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Krysan
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D003453:Cryptococcosis / Q000188:drug therapy*; D003455:Cryptococcus neoformans / Q000187:drug effects*; D004357:Drug Synergism; D015725:Fluconazole / Q000494:pharmacology*; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008826:Microbial Sensitivity Tests; D010330:Patents as Topic; D010586:Phagocytes / Q000382:microbiology; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013468:Suloctidil / Q000494:pharmacology; D013881:Thioridazine / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D002147:Calmodulin; D005656:Fungal Proteins; D054852:Small Molecule Libraries; D015725:Fluconazole; D000263:Adenylate Kinase; D013881:Thioridazine; D000638:Amiodarone; D013468:Suloctidil