Journal of global antimicrobial resistance · 2017
Fluconazole inhibits cellular ergosterol synthesis to confer synergism with berberine against yeast cells.
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Yang Zhanju, Wang Qiao, Ma Ke, Shi Ping, Liu Wenbin, Huang Zhiwei
Аннотация
OBJECTIVES: 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.
METHODS: Biochemical and genetic analyses were performed to investigate the probable antifungal role of the combined use of BBR and FLC in S. cerevisiae.
RESULTS: 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.
CONCLUSIONS: FLC enhances cell membrane permeability via inhibition of cellular ergosterol synthesis, thus assisting BBR to kill fungal cells.
METHODS: Biochemical and genetic analyses were performed to investigate the probable antifungal role of the combined use of BBR and FLC in S. cerevisiae.
RESULTS: 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.
CONCLUSIONS: FLC enhances cell membrane permeability via inhibition of cellular ergosterol synthesis, thus assisting BBR to kill fungal cells.