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Synergistic effect of calcineurin inhibitors and fluconazole against Candida albicans biofilms.

Publication ,  Journal Article
Uppuluri, P; Nett, J; Heitman, J; Andes, D
Published in: Antimicrob Agents Chemother
March 2008

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.

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Published In

Antimicrob Agents Chemother

DOI

ISSN

0066-4804

Publication Date

March 2008

Volume

52

Issue

3

Start / End Page

1127 / 1132

Location

United States

Related Subject Headings

  • Tacrolimus
  • Rats
  • Microbiology
  • Microbial Sensitivity Tests
  • Humans
  • Fluconazole
  • Drug Synergism
  • Drug Resistance, Fungal
  • Cyclosporine
  • Candida albicans
 

Citation

APA
Chicago
ICMJE
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Uppuluri, P., Nett, J., Heitman, J., & Andes, D. (2008). Synergistic effect of calcineurin inhibitors and fluconazole against Candida albicans biofilms. Antimicrob Agents Chemother, 52(3), 1127–1132. https://doi.org/10.1128/AAC.01397-07
Uppuluri, Priya, Jeniel Nett, Joseph Heitman, and David Andes. “Synergistic effect of calcineurin inhibitors and fluconazole against Candida albicans biofilms.Antimicrob Agents Chemother 52, no. 3 (March 2008): 1127–32. https://doi.org/10.1128/AAC.01397-07.
Uppuluri P, Nett J, Heitman J, Andes D. Synergistic effect of calcineurin inhibitors and fluconazole against Candida albicans biofilms. Antimicrob Agents Chemother. 2008 Mar;52(3):1127–32.
Uppuluri, Priya, et al. “Synergistic effect of calcineurin inhibitors and fluconazole against Candida albicans biofilms.Antimicrob Agents Chemother, vol. 52, no. 3, Mar. 2008, pp. 1127–32. Pubmed, doi:10.1128/AAC.01397-07.
Uppuluri P, Nett J, Heitman J, Andes D. Synergistic effect of calcineurin inhibitors and fluconazole against Candida albicans biofilms. Antimicrob Agents Chemother. 2008 Mar;52(3):1127–1132.

Published In

Antimicrob Agents Chemother

DOI

ISSN

0066-4804

Publication Date

March 2008

Volume

52

Issue

3

Start / End Page

1127 / 1132

Location

United States

Related Subject Headings

  • Tacrolimus
  • Rats
  • Microbiology
  • Microbial Sensitivity Tests
  • Humans
  • Fluconazole
  • Drug Synergism
  • Drug Resistance, Fungal
  • Cyclosporine
  • Candida albicans