Abstract
The effectiveness of the potent antifungal drug fluconazole is being compromised by the rise of drug-resistant fungal pathogens. While inhibition of Hsp90 or calcineurin can reverse drug resistance in Candida, such inhibitors also impair the homologous human host protein and fungal-selective chemosensitizers remain rare. The MLPCN library was screened to identify compounds that selectively reverse fluconazole resistance in a Candida albicans clinical isolate, while having no antifungal activity when administered as a single agent. A piperazinyl quinoline was identified as a new small-molecule probe (ML189) satisfying these criteria.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antifungal Agents / chemistry
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Antifungal Agents / pharmacology*
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Calcineurin / metabolism
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Calcineurin Inhibitors*
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Candida albicans / drug effects*
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Candida albicans / growth & development
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Candida albicans / isolation & purification
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Dose-Response Relationship, Drug
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Fluconazole / chemistry
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Fluconazole / pharmacology*
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / metabolism
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Microbial Sensitivity Tests
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Molecular Structure
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Quinolines / chemical synthesis
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Quinolines / chemistry
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Quinolines / pharmacology*
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Small Molecule Libraries
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Antifungal Agents
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Calcineurin Inhibitors
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HSP90 Heat-Shock Proteins
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Quinolines
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Small Molecule Libraries
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Fluconazole
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Calcineurin