A repurposing approach identifies off-patent drugs with fungicidal cryptococcal activity, a common structural chemotype, and pharmacological properties relevant to the treatment of Cryptococcosis

Arielle Butts, Louis DiDone, Kristy Koselny, Bonnie K. Baxter, Yeissa Chabrier-Rosello, Melanie Wellington, Damian J. Krysanb

Research output: Contribution to journalArticle

34 Citations (Scopus)

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 highthroughput 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 bloodbrain 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.

Original languageEnglish (US)
Pages (from-to)278-287
Number of pages10
JournalEukaryotic Cell
Volume12
Issue number2
DOIs
StatePublished - Feb 1 2013

Fingerprint

Cryptococcosis
Pharmacology
Cryptococcus neoformans
Pharmaceutical Preparations
Calmodulin
Thioridazine
Phagosomes
Amiodarone
Fluconazole
Blood-Brain Barrier
Amines
Fungi

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Molecular Biology

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A repurposing approach identifies off-patent drugs with fungicidal cryptococcal activity, a common structural chemotype, and pharmacological properties relevant to the treatment of Cryptococcosis. / Butts, Arielle; DiDone, Louis; Koselny, Kristy; Baxter, Bonnie K.; Chabrier-Rosello, Yeissa; Wellington, Melanie; Krysanb, Damian J.

In: Eukaryotic Cell, Vol. 12, No. 2, 01.02.2013, p. 278-287.

Research output: Contribution to journalArticle

Butts, Arielle ; DiDone, Louis ; Koselny, Kristy ; Baxter, Bonnie K. ; Chabrier-Rosello, Yeissa ; Wellington, Melanie ; Krysanb, Damian J. / A repurposing approach identifies off-patent drugs with fungicidal cryptococcal activity, a common structural chemotype, and pharmacological properties relevant to the treatment of Cryptococcosis. In: Eukaryotic Cell. 2013 ; Vol. 12, No. 2. pp. 278-287.
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