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Antimicrobial Agents and Chemotherapy, March 2008, p. 1127-1132, Vol. 52, No. 3
0066-4804/08/$08.00+0     doi:10.1128/AAC.01397-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Synergistic Effect of Calcineurin Inhibitors and Fluconazole against Candida albicans Biofilms{triangledown}

Priya Uppuluri,1 Jeniel Nett,2 Joseph Heitman,1* and David Andes2*

Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710,1 Department of Medicine, University of Wisconsin, Madison, Wisconsin 537922

Received 29 October 2007/ Returned for modification 8 December 2007/ Accepted 21 December 2007

Calcineurin is a Ca2+-calmodulin-activated serine/threonine-specific protein phosphatase that governs multiple aspects of fungal physiology, including cation homeostasis, morphogenesis, antifungal drug susceptibility, and virulence. Growth of Candida albicans planktonic cells is sensitive to the calcineurin inhibitors FK506 and cyclosporine A (CsA) in combination with the azole antifungal fluconazole. This drug synergism is attributable to two effects: first, calcineurin inhibitors render fluconazole fungicidal rather than simply fungistatic, and second, membrane perturbation by azole inhibition of ergosterol biosynthesis increases intracellular calcineurin inhibitor concentrations. C. albicans cells in biofilms are up to 1,000-fold more resistant to fluconazole than planktonic cells. In both in vitro experiments and in an in vivo rat catheter model, C. albicans cells in biofilms were resistant to individually delivered fluconazole or calcineurin inhibitors but exquisitely sensitive to the combination of FK506-fluconazole or CsA-fluconazole. C. albicans strains lacking FKBP12 or expressing a dominant FK506-resistant calcineurin mutant subunit (Cnb1-1) formed biofilms that were resistant to FK506-fluconazole but susceptible to CsA-fluconazole, demonstrating that drug synergism is mediated via direct calcineurin inhibition. These findings reveal that calcineurin contributes to fluconazole resistance of biofilms and provide evidence that synergistic drug combinations may prove efficacious as novel therapeutic interventions to treat or prevent biofilms.

* Corresponding author. Mailing address for J. Heitman: Box 3546, 322 CARL Bldg., Research Dr., Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-2824. Fax: (919) 684-5458. E-mail: heitm001{at}duke.edu. Mailing address for D. Andes: 600 Highland Ave., Room H4.572, Madison, WI 53792. Phone: (608) 263-1545. Fax: (608) 263-4464. E-mail: dra{at}medicine.wisc.edu

{triangledown} Published ahead of print on 7 January 2008.

Antimicrobial Agents and Chemotherapy, March 2008, p. 1127-1132, Vol. 52, No. 3
0066-4804/08/$08.00+0     doi:10.1128/AAC.01397-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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