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Infection and Immunity, July 2006, p. 3804-3816, Vol. 74, No. 7
0019-9567/06/$08.00+0     doi:10.1128/IAI.00161-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Alcohol Dehydrogenase Restricts the Ability of the Pathogen Candida albicans To Form a Biofilm on Catheter Surfaces through an Ethanol-Based Mechanism

Pranab K. Mukherjee,¹ Sotohy Mohamed,¹ Jyotsna Chandra,¹ Duncan Kuhn,^1, Shuqing Liu,² Omar S. Antar,³ Ryan Munyon,¹ Aaron P. Mitchell,³ David Andes,⁴ Mark R. Chance,² Mahmoud Rouabhia,⁵ and Mahmoud A. Ghannoum^1*

Center for Medical Mycology, Case Western Reserve University, Cleveland, Ohio,¹ Center for Proteomics, Case Western Reserve University, Cleveland, Ohio,² Department of Microbiology, Columbia University, New York, New York,³ Department of Medicine, University of Wisconsin, Madison, Wisconsin,⁴ Groupe de Recherche en Ecologie Buccale, Faculte de Medecine Dentaire, Universite Laval, Quebec City, Quebec, Canada⁵

Received 30 January 2006/ Returned for modification 28 February 2006/ Accepted 25 March 2006

Candida biofilms formed on indwelling medical devices are increasingly associated with severe infections. In this study, we used proteomics and Western and Northern blotting analyses to demonstrate that alcohol dehydrogenase (ADH) is downregulated in Candida biofilms. Disruption of ADH1 significantly (P = 0.0046) enhanced the ability of Candida albicans to form biofilm. Confocal scanning laser microscopy showed that the adh1 mutant formed thicker biofilm than the parent strain (210 µm and 140 µm, respectively). These observations were extended to an engineered human oral mucosa and an in vivo rat model of catheter-associated biofilm. Inhibition of Candida ADH enzyme using disulfiram and 4-methylpyrazole resulted in thicker biofilm (P < 0.05). Moreover, biofilms formed by the adh1 mutant strain produced significantly smaller amounts of ethanol, but larger amounts of acetaldehyde, than biofilms formed by the parent and revertant strains (P < 0.0001), demonstrating that the effect of Adh1p on biofilm formation is mediated by its enzymatic activity. Furthermore, we found that 10% ethanol significantly inhibited biofilm formation in vitro, with complete inhibition of biofilm formation at ethanol concentrations of 20%. Similarly, using a clinically relevant rabbit model of catheter-associated biofilm, we found that ethanol treatment inhibited biofilm formation by C. albicans in vivo (P < 0.05) but not by Staphylococcus spp. (P > 0.05), indicating that ethanol specifically inhibits Candida biofilm formation. Taken together, our studies revealed that Adh1p contributes to the ability of C. albicans to form biofilms in vitro and in vivo and that the protein restricts biofilm formation through an ethanol-dependent mechanism. These results are clinically relevant and may suggest novel antibiofilm treatment strategies.

Supplemental material for this article may be found at http://iai.asm.org/.

Editor: A. Casadevall

Present address: Division of Pulmonary and Critical Care, Massachusetts General Hospital, Boston, MA 02114.

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