Fluconazole inhibits cellular ergosterol synthesis to confer synergism with berberine against yeast cells.

Abstract

Although berberine (BBR) is reported to exhibit weak activity against Candida albicans, combined use of BBR and fluconazole (FLC) showed synergism against FLC-resistant C. albicans in vitro. The aim of this study was to explore the synergistic antifungal mechanism of FLC and BBR in Saccharomyces cerevisiae, a typical fungal cell model. Biochemical and genetic analyses were performed to investigate the probable antifungal role of the combined use of BBR and FLC in S. cerevisiae. FLC led to elevated cell membrane permeability in the wild-type S. cerevisiae BY4741, similar to the sterol synthesis-deficient strains erg2Δ and erg6Δ. Biochemical analysis indicated that FLC significantly inhibited cellular ergosterol synthesis, leading to a decrease in cell membrane stability, which increased the rate of BBR uptake and utilisation and reduced the inhibitory concentrations of BBR in wild-type yeast cells. Genetic analysis of the inhibitory effect of FLC and BBR on sterol synthesis-deficient (erg2Δ and erg6Δ) and DNA damage repair defect (rad1Δ) strains showed that FLC and BBR possess different antifungal mechanisms. FLC enhances cell membrane permeability via inhibition of cellular ergosterol synthesis, thus assisting BBR to kill fungal cells.