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ACS Chem Biol. 2013 Apr 19;8(4):840-8. doi: 10.1021/cb400009f. Epub 2013 Feb 14.

Small-molecule suppressors of Candida albicans biofilm formation synergistically enhance the antifungal activity of amphotericin B against clinical Candida isolates.

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1
Natural Products Discovery Group, Institute for Natural Products Applications and Research Technologies, Stephenson Life Sciences Research Center, 101 Stephenson Parkway, University of Oklahoma, Norman, OK 73019-5251, USA.

Abstract

A new class of fungal biofilm inhibitors represented by shearinines D (3) and E (4) were obtained from a Penicillium sp. isolate. The inhibitory activities of 3 and 4 were characterized using a new imaging flow-cytometer technique, which enabled the rapid phenotypic analysis of Candida albicans cell types (budding yeast cells, germ tube cells, pseudohyphae, and hyphae) in biofilm populations. The results were confirmed by experimental data obtained from three-dimensional confocal laser scanning microscopy and 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assays. These data indicate that 3 and 4 inhibited C. albicans biofilm formation by blocking the outgrowth of hyphae at a relatively late stage of biofilm development (IC50 = 8.5 and 7.6 μM, respectively). However, 3 and 4 demonstrated comparatively weak activity at disrupting existing biofilms. Compounds 3 and 4 also exhibited synergistic activities with amphotericin B against C. albicans and other clinical Candida isolates by enhancing the potency of amphotericin B up to 8-fold against cells in both developing and established biofilms. These data suggest that the Candida biofilm disruption and amphotericin B potentiating effects of 3 and 4 could be mediated through multiple biological targets. The shearinines are good tools for testing the potential advantages of using adjunctive therapies in combination with antifungals.

PMID:
23387427
PMCID:
PMC3631451
DOI:
10.1021/cb400009f
[Indexed for MEDLINE]
Free PMC Article
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