1887

Abstract

There is an increasing concern about due to its high isolation frequency in candidiasis recently and notorious drug resistance to fluconazole. Drug combination is one effective approach to counteract drug resistance. This study aimed to test whether a combination of fluconazole and tacrolimus (FK506) had a synergistic effect on , and to seek the potential mechanisms underlying the synergistic effects. effects of fluconazole and FK506 against with different susceptibilities were investigated by a chequerboard method and a time–kill curve method. The mechanistic studies against the resistant were performed from two aspects: quantification of expression levels of fluconazole resistance genes (, , and ) by real-time quantitative PCR and functional assays of drug efflux pumps. The addition of FK506 resulted in a decrease in the MIC of fluconazole from 32 to 8 µg ml against the dose-dependent susceptible , and from 256 to 16 µg ml against the resistant , respectively. The synergy was further confirmed by the time-kill assay. The expression levels of the and genes were significantly downregulated after exposure to the drug combination, whereas that of the gene was significantly upregulated, and no significant change in expression of gene was observed. Flow cytometric assays showed that FK506 reduced the efflux of fluconazole. Tacrolimus enhanced the susceptibility of fluconazole against resistant by reducing the expression levels of the and genes and inhibiting fluconazole efflux.

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2015-01-01
2019-12-06
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