Abstract
BackgroundBiofilms produced by Candida albicans (C. albicans) are intrinsically resistant to fungicidal agents, which are a main cause of the pathogenesis of catheter infections. Several lines of evidence have demonstrated that calcineurin inhibitor FK506 or cyclosporine A (CsA) can remarkably enhance the antifungal activity of fluconazole (FLC) against biofilm-producing C. albicans strain infections. The aim of present study is thus to interrogate the mechanism underpinning the synergistic effect of FLC and calcineurin inhibitors.ResultsTwenty four clinical C. albicans strains isolated from bloodstream showed a distinct capacity of biofilm formation. A combination of calcineurin inhibitor CsA and FLC exhibited a dose-dependent synergistic antifungal effect on the growth and biofilm formation of C. albicans isolates as determined by a XTT assay and fluorescent microscopy assay. The synergistic effect was accompanied with a significantly down-regulated expression of adhesion-related genes ALS3, hypha-related genes HWP1, ABC transporter drug-resistant genes CDR1 and MDR1, and FLC targeting gene, encoding sterol 14alpha-demethylase (ERG11) in clinical C. albicans isolates. Furthermore, an addition of CsA significantly reduced the cellular surface hydrophobicity but increased intracellular calcium concentration as determined by a flow cytometry assay (p < 0.05).ConclusionThe results presented in this report demonstrated that the synergistic effect of CsA and FLC on inhibited C. albicans biofilm formation and enhanced susceptibility to FLC was in part through a mechanism involved in suppressing the expression of biofilm related and drug-resistant genes, and reducing cellular surface hydrophobicity, as well as evoking intracellular calcium concentration.
Highlights
Biofilms produced by Candida albicans (C. albicans) are intrinsically resistant to fungicidal agents, which are a main cause of the pathogenesis of catheter infections
The result showed distinct biofilm-producing capacities of these clinical isolates, which could be categorized into three groups, strain with capacity of low biofilm formation (LBF), intermediate biofilm formation (IBF) and high biofilm formation (HBF), according the absorbance of OD590nm as described as previous report [25]. 6 clinical isolates were fell into LBF with an OD590nm value less than the first quartile (Q1 OD590nm = 0.384), 12 strains in HBF with an OD590nm value greater than the third quartile (Q3 OD590nm = 1.152), and 6 strains could be grouped in IBF with an OD590nm value between Q1 and Q2 in this report (Fig. 1a)
cyclosporine A (CsA) enhances the susceptibility of clinical biofilmproducing Candida albicans to fluconazole Calcineurin inhibitors, such as FK506 and CsA have been evidenced to enhance the susceptibility of C. albicans to azole agents [14, 17, 18]
Summary
Biofilms produced by Candida albicans (C. albicans) are intrinsically resistant to fungicidal agents, which are a main cause of the pathogenesis of catheter infections. Several lines of evidence have demonstrated that calcineurin inhibitor FK506 or cyclosporine A (CsA) can remarkably enhance the antifungal activity of fluconazole (FLC) against biofilm-producing C. albicans strain infections. The calcineurin inhibitor CsA was recently found to be able to enhance the susceptibility of biofilm-producing C. albicans to fluconazole [24]. These results implied that targeting calcineurin signaling using a combination of calcineurin inhibitor FK506 or CsA and FLC might be a promising antifungal strategy for prevention and treatment of biofilm C. albicans infection. The underlying mechanism by which a calcineurin inhibitor enhances the susceptibility of C. albicans to the most common antifungal agent, FLC has yet been fully understood
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