The calcineruin inhibitor cyclosporine a synergistically enhances the susceptibility of Candida albicans biofilms to fluconazole by multiple mechanisms.
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 aim of present study is thus to interrogate the mechanism underpinning the synergistic effect of FLC and calcineurin inhibitors.



Twenty 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).



The 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.
Ningxia Key laboratory of Clinical and Pathogenic Microbiology, the General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, China.|Center of Laboratory Medicine, the General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, China.
Wei
W
Jia
The First People's Hospital of Mudanjiang City, Mudanjiang, Helongjiang, 157011, China.
Haiyun
H
Zhang
Department of Laboratory Medicine, College of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia, 750004, China.
Caiyun
C
Li
Ningxia Key laboratory of Clinical and Pathogenic Microbiology, the General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, China.|Center of Laboratory Medicine, the General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, China.
Gang
G
Li
Ningxia Key laboratory of Clinical and Pathogenic Microbiology, the General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, China. liuxiaoming@nxmu.edu.cn.
Xiaoming
X
Liu
Ningxia Key laboratory of Clinical and Pathogenic Microbiology, the General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, China. weijun@nxmu.edu.cn.|Center of Laboratory Medicine, the General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, China. weijun@nxmu.edu.cn.
Jun
J
Wei
D000935:Antifungal Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D065095:Calcineurin Inhibitors / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology; D002177:Candidiasis / Q000382:microbiology; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D025141:Drug Resistance, Fungal; D004357:Drug Synergism; D015725:Fluconazole / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D016559:Tacrolimus / Q000494:pharmacology
D000935:Antifungal Agents; D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D015725:Fluconazole; D016559:Tacrolimus
Biofilm; Calcineurin inhibitor; Candida albicans; Cyclosporine A; Fluconazole