Synergistic effect of calcineurin inhibitors and fluconazole against Candida albicans biofilms

被引:170
|
作者
Uppuluri, Priya [1 ]
Nett, Jeniel [2 ]
Heitman, Joseph [1 ]
Andes, David [2 ]
机构
[1] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA
[2] Univ Wisconsin, Dept Med, Madison, WI 53792 USA
关键词
D O I
10.1128/AAC.01397-07
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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.
引用
收藏
页码:1127 / 1132
页数:6
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