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A Small Subpopulation of Blastospores in Candida albicans Biofilms Exhibit Resistance to Amphotericin B Associated with Differential Regulation of Ergosterol and ß-1,6-Glucan Pathway Genes

Prasanna D. Khot,^1, Peter A. Suci,^2* R. Lance Miller,³ Raoul D. Nelson,³ and Bonnie J. Tyler^1*

Department of Chemical Engineering, University of Utah, Salt Lake City, Utah 84112,¹ Department of Microbiology and Center for Biofilm Engineering, Montana State University, Bozeman, Montana 59717,² Department of Pediatrics, Division of Nephrology, School of Medicine, University of Utah, Salt Lake City, Utah 84132³

Received 10 August 2006/ Accepted 1 September 2006

The resistance of Candida albicans biofilms to a broad spectrum of antimicrobial agents has been well documented. Biofilms are known to be heterogeneous, consisting of microenvironments that may induce formation of resistant subpopulations. In this study we characterized one such subpopulation. C. albicans biofilms were cultured in a tubular flow cell (TF) for 36 h. The relatively large shear forces imposed by draining the TF removed most of the biofilm, which consisted of a tangled mass of filamentous forms with associated clusters of yeast forms. This portion of the biofilm exhibited the classic architecture and morphological heterogeneity of a C. albicans biofilm and was only slightly more resistant than either exponential- or stationary-phase planktonic cells. A submonolayer fraction of blastospores that remained on the substratum was resistant to 10 times the amphotericin B dose that eliminated the activity of the planktonic populations. A comparison between planktonic and biofilm populations of transcript abundance for genes coding for enzymes in the ergosterol (ERG1, -3, -5, -6, -9, -11, and -25) and ß-1,6-glucan (SKN and KRE1, -5, -6, and -9) pathways was performed by quantitative RT-PCR. The results indicate a possible association between the high level of resistance exhibited by the blastospore subpopulation and differential regulation of ERG1, ERG25, SKN1, and KRE1. We hypothesize that the resistance originates from a synergistic effect involving changes in both the cell membrane and the cell wall.

Published ahead of print on 11 September 2006.

Present address: Fred Hutchinson Cancer Research Center, Program in Infectious Diseases, D3-100, Seattle, WA 98109-1024.

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