{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:35:14Z","timestamp":1791297314405,"version":"4.1.0"},"reference-count":42,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2013,2,1]],"date-time":"2013-02-01T00:00:00Z","timestamp":1359676800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Eukaryot Cell"],"published-print":{"date-parts":[[2013,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    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\n                    <jats:named-content content-type=\"genus-species\">Cryptococcus neoformans<\/jats:named-content>\n                    , 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\n                    <jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>\n                    . 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\n                    <jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>\n                    . Finally, the set of drugs is also enriched for molecules that inhibit calmodulin, and we have confirmed that seven drugs directly bind\n                    <jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>\n                    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.\n                  <\/jats:p>","DOI":"10.1128\/ec.00314-12","type":"journal-article","created":{"date-parts":[[2012,12,15]],"date-time":"2012-12-15T21:04:45Z","timestamp":1355605485000},"page":"278-287","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":93,"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"],"prefix":"10.1128","volume":"12","author":[{"given":"Arielle","family":"Butts","sequence":"first","affiliation":[{"name":"Departments of Chemistry, University of Rochester, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"DiDone","sequence":"additional","affiliation":[{"name":"Pediatrics, University of Rochester, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristy","family":"Koselny","sequence":"additional","affiliation":[{"name":"Pediatrics, University of Rochester, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bonnie K.","family":"Baxter","sequence":"additional","affiliation":[{"name":"Pediatrics, University of Rochester, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeissa","family":"Chabrier-Rosello","sequence":"additional","affiliation":[{"name":"Pediatrics, University of Rochester, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Wellington","sequence":"additional","affiliation":[{"name":"Pediatrics, University of Rochester, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damian J.","family":"Krysan","sequence":"additional","affiliation":[{"name":"Pediatrics, University of Rochester, Rochester, New York, USA"},{"name":"Microbiology\/Immunology, University of Rochester, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0b013e328322ffac"},{"key":"e_1_3_2_3_2","first-page":"3","volume-title":"Cryptococcus: from human pathogen to model yeast","author":"Kwon-Chung KJ","year":"2011","unstructured":"Kwon-ChungKJ BoekhoutT WickesBL FellJ. 2011. Systematics of the genus Cryptococcus and its type species C. neoformans, p 3\u201317. In HeitmanJ KozelTR Kwon-ChungKJ PerfectJR CasadevallA (ed), Cryptococcus: from human pathogen to model yeast. ASM Press, Washington, DC."},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00165-12"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1086\/649858"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1097\/QCO.0b013e32832fa214"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1086\/604716"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002870"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2010.47"},{"key":"e_1_3_2_10_2","first-page":"1883","volume-title":"Curr. Top. Med. Chem.","author":"Bisson WH","year":"2012","unstructured":"BissonWH. 2012. Drug repurposing in chemical genomics: can we learn from the past to improve the future? Curr. Top. Med. 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