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Identification of inhibitors of yeast-to-hyphae transition in Candida albicans by a reporter screening assay

Paper ID Volume ID Publish Year Pages File Format Full-Text
23572 43452 2013 6 PDF Available
Title
Identification of inhibitors of yeast-to-hyphae transition in Candida albicans by a reporter screening assay
Abstract

Candida albicans is one of the most common opportunistic fungal pathogens, causing life-threatening disease in immunocompromised patients. As it is not primarily a pathogen, but can exist in a commensal state, we aimed at the identification of new anti-infective compounds which do not eradicate the fungus, but primarily disable a virulence determinant. The yeast–hyphae-dimorphism of C. albicans is considered a major contributor to fungal disease, as mutants locked into either yeast or hyphal state have been shown to be less virulent in the mouse-model.We devised a high-throughput screening procedure which allows us to find inhibitors of the induction of hyphae. Hyphae-formation was induced by nitrogen starvation at 37 °C and neutral pH in a reporter strain, which couples promoter activity of the hyphae-specific HWP1 to β-galactosidase expression. In a pilot screening of 720 novel synthetic compounds, we identified substances which inhibited the outgrowth of germ tubes. They belonged to chemical classes not yet known for antimycotic properties, namely methyl aryl-oxazoline carboxylates, dihydrobenzo[d]isoxazolones and thiazolo[4,5-e]benzoisoxazoles.In conclusion we developed a novel screening assay, which addresses the morphological switch from the yeast form of C. albicans to its hyphal form and identified novel chemical structures with activity against C. albicans.

► The yeast–hyphae-dimorphism is a major virulence factor of Candida albicans. ► A reporter assay was optimised to detect hyphal inhibitors in an automated setting. ► A pilot screening of a collection of novel compounds was carried out. ► Three new classes of antimycotic components were identified.

Keywords
HWP, hyphal wall protein; MTT, 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide; ONPG, o-nitrophenyl-β-d-galactoside; YNB, yeast nitrogen base; SLAD, synthetic low ammonium dextroseReporter strain; Beta-galactosidase; HWP1; Morphology
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Identification of inhibitors of yeast-to-hyphae transition in Candida albicans by a reporter screening assay
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Publisher
Database: Elsevier - ScienceDirect
Journal: Journal of Biotechnology - Volume 164, Issue 1, 10 March 2013, Pages 137–142
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us