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Genome-Wide Fitness Test and Mechanism-of-Action Studies of Inhibitory Compounds in Candida albicans

Title:

Genome-Wide Fitness Test and Mechanism-of-Action Studies of Inhibitory Compounds in Candida albicans

Xu, Deming and Jiang, Bo and Ketela, Troy and Lemieux, Sebastien and Veillette, Karynn and Martel, Nick and Davison, John and Sillaots, Susan and Trosok, Steve and Bachewich, Catherine and Bussey, Howard and Youngman, Phil and Roemer, Terry (2007) Genome-Wide Fitness Test and Mechanism-of-Action Studies of Inhibitory Compounds in Candida albicans. PLoS Pathogens, 3 (6). e92. ISSN 1553-7366

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Official URL: http://dx.doi.org/10.1371/journal.ppat.0030092

Abstract

Candida albicans is a prevalent fungal pathogen amongst the immunocompromised population, causing both superficial and life-threatening infections. Since C. albicans is diploid, classical transmission genetics can not be performed to study specific aspects of its biology and pathogenesis. Here, we exploit the diploid status of C. albicans by constructing a library of 2,868 heterozygous deletion mutants and screening this collection using 35 known or novel compounds to survey chemically induced haploinsufficiency in the pathogen. In this reverse genetic assay termed the fitness test, genes related to the mechanism of action of the probe compounds are clearly identified, supporting their functional roles and genetic interactions. In this report, chemical–genetic relationships are provided for multiple FDA-approved antifungal drugs (fluconazole, voriconazole, caspofungin, 5-fluorocytosine, and amphotericin B) as well as additional compounds targeting ergosterol, fatty acid and sphingolipid biosynthesis, microtubules, actin, secretion, rRNA processing, translation, glycosylation, and protein folding mechanisms. We also demonstrate how chemically induced haploinsufficiency profiles can be used to identify the mechanism of action of novel antifungal agents, thereby illustrating the potential utility of this approach to antifungal drug discovery.

Divisions:Concordia University > Faculty of Arts and Science > Biology
Item Type:Article
Refereed:Yes
Authors:Xu, Deming and Jiang, Bo and Ketela, Troy and Lemieux, Sebastien and Veillette, Karynn and Martel, Nick and Davison, John and Sillaots, Susan and Trosok, Steve and Bachewich, Catherine and Bussey, Howard and Youngman, Phil and Roemer, Terry
Journal or Publication:PLoS Pathogens
Date:29 June 2007
ID Code:7579
Deposited By:DANIELLE DENNIE
Deposited On:11 May 2011 17:12
Last Modified:11 May 2011 17:12
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