Antifungal activity and potential mechanism of berberine hydrochloride against fluconazole-resistant Candida albicans

Abstract

Introduction. The emergence of resistance to fluconazole in Candida albicans has made the clinical treatment of this microbe difficult. A potential strategy to address this problem involves diminishing fungal resistance to antimicrobial drugs. Hypothesis. Berberine hydrochloride (BH), the primary active ingredient of the traditional Chinese medicine (TCM) Coptis, inhibits the growth of fluconazole-resistant C. albicans through its action on the high-osmolarity glycerol mitogen-activated protein kinase (HOG-MAPK) pathway. Aim. To examine the effect of BH on the HOG-MAPK pathway to assess the potential molecular mechanism by which BH inhibits fluconazole-resistant C. albicans. Methodology. The minimum inhibitory concentration (MIC) of BH to fluconazole-resistant C. albicans was measured using the broth microdilution approach to determine the concentration of effective drug intervention. Changes in physiological functions regulated by the HOG-MAPK pathway in response to BH treatment were measured, as well as the expression of central signalling pathway genes and key downstream factors by qRT-PCR and Western blotting, respectively. Results. BH inhibited fluconazole-resistant C. albicans and the sensitivity to fluconazole increased after BH treatment. At a concentration of 256 and 64 μg ml−1 BH may affect key downstream factors that regulate several physiological functions of C. albicans by upregulating the core genes expression of SLN1, SSK2, HOG1, and PBS2 in the HOG-MAPK pathway. Upregulation of GPD1, the key gene for glycerol synthesis, increased cell osmotic pressure. BH treatment increased the accumulation of reactive oxygen species by upregulating the expression of the key respiratory metabolism gene ATP11 and downregulating the expression of the superoxide dismutase gene SOD2. Furthermore, downregulation of mycelial-specific HWP1 hindered the morphological transformation of C. albicans and inhibition of the chitin synthase gene CHS3 and the β-(1,3) glucan synthase gene GSC1 impaired cytoderm integrity. Conclusion. BH affects multiple target genes in diminishing the resistance of C. albicans strains to fluconazole. This effect may be related to the action of BH on the HOG-MAPK pathway.

The potential role of plant secondary metabolites on antifungal and immunomodulatory effect

“…Berberine, isolated from Coptis chinensis and Phellodendron chinense , exerted an antifungal effect on C. albicans by upregulating the expression of core genes ( sln1 , ssk2 , hog1 , and pbs2 ) and inducing ROS accumulation and inhibiting the expression of the chitin synthase gene ( chs3 ) and the β-(1,3)-glucan synthase gene ( gsc1 ) to damage the integrity of the cytoplasm, inhibit the formation of germ tubes and hyphae, and destroy the integrity of cell wall (Huang et al 2021 ). Berberine also exerted synergistic antifungal spread ability in vivo when combined with AmB or FLC; when berberine was combined with AmB, the survival time of mice with disseminated infection of pathogenic C. albicans was increased from 14 to 36 d (Huang et al 2022 ; Quan et al 2006 ).…”

The effect of herbal medicine in innate immunity to Candida albicans

“…As far as antifungal is concerned, berberine can either directly inhibit C. albicans or act as a sensitizer to enhance the antibacterial effect of FLU against C. albicans. C. albicans is susceptible to resistance to commonly used antifungal drugs such as fluconazole and amphotericin B (72). Berberine was found to inhibit fluconazole-resistant C. albicans through its action on the highosmolarity glycerol mitogen-activated protein kinase (HOG-MAPK) pathway, with increased susceptibility to fluconazole after treatment (73).…”