This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Uppuluri, P.
Right arrow Articles by Andes, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Uppuluri, P.
Right arrow Articles by Andes, D.

 Previous Article  |  Next Article 

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.



This article has been cited by other articles:

  • Dannaoui, E., Schwarz, P., Lortholary, O. (2009). In Vitro Interactions between Antifungals and Immunosuppressive Drugs against Zygomycetes. Antimicrob. Agents Chemother. 53: 3549-3551 [Abstract] [Full Text]  
  • Guo, N., Liu, J., Wu, X., Bi, X., Meng, R., Wang, X., Xiang, H., Deng, X., Yu, L. (2009). Antifungal activity of thymol against clinical isolates of fluconazole-sensitive and -resistant Candida albicans. J Med Microbiol 58: 1074-1079 [Abstract] [Full Text]  
  • Toenjes, K. A., Stark, B. C., Brooks, K. M., Johnson, D. I. (2009). Inhibitors of cellular signalling are cytotoxic or block the budded-to-hyphal transition in the pathogenic yeast Candida albicans. J Med Microbiol 58: 779-790 [Abstract] [Full Text]  
  • Cannon, R. D., Lamping, E., Holmes, A. R., Niimi, K., Baret, P. V., Keniya, M. V., Tanabe, K., Niimi, M., Goffeau, A., Monk, B. C. (2009). Efflux-Mediated Antifungal Drug Resistance. Clin. Microbiol. Rev. 22: 291-321 [Abstract] [Full Text]  
  • Semighini, C. P., Heitman, J. (2009). Dynamic duo takes down fungal villains. Proc. Natl. Acad. Sci. USA 106: 2971-2972 [Full Text]  
  • ten Cate, J.M., Klis, F.M., Pereira-Cenci, T., Crielaard, W., de Groot, P.W.J. (2009). Molecular and Cellular Mechanisms That Lead to Candida Biofilm Formation. JDR 88: 105-115 [Abstract] [Full Text]  
  • Holmes, A. R., Lin, Y.-H., Niimi, K., Lamping, E., Keniya, M., Niimi, M., Tanabe, K., Monk, B. C., Cannon, R. D. (2008). ABC Transporter Cdr1p Contributes More than Cdr2p Does to Fluconazole Efflux in Fluconazole-Resistant Candida albicans Clinical Isolates. Antimicrob. Agents Chemother. 52: 3851-3862 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»