Journal article
A Repurposing Approach Identifies Off-Patent Drugs with Fungicidal Cryptococcal Activity, a Common Structural Chemotype, and Pharmacological Properties Relevant to the Treatment of Cryptococcosis
Eukaryotic cell, Vol.12(2), pp.278-287
02/2013
DOI: 10.1128/EC.00314-12
PMCID: PMC3571299
PMID: 23243064
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.
Details
- Title: Subtitle
- A Repurposing Approach Identifies Off-Patent Drugs with Fungicidal Cryptococcal Activity, a Common Structural Chemotype, and Pharmacological Properties Relevant to the Treatment of Cryptococcosis
- Creators
- Arielle Butts - Departments of ChemistryLouis DiDone - PediatricsKristy Koselny - PediatricsBonnie K Baxter - PediatricsYeissa Chabrier-Rosello - PediatricsMelanie Wellington - PediatricsDamian J Krysan - Pediatrics
- Resource Type
- Journal article
- Publication Details
- Eukaryotic cell, Vol.12(2), pp.278-287
- DOI
- 10.1128/EC.00314-12
- PMID
- 23243064
- PMCID
- PMC3571299
- NLM abbreviation
- Eukaryot Cell
- ISSN
- 1535-9778
- eISSN
- 1535-9786
- Publisher
- American Society for Microbiology
- Language
- English
- Date published
- 02/2013
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
- Record Identifier
- 9984093371402771
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