How Berberine Boosts Fluconazole to Fight Drug-Resistant Yeast Infections

Jenn Hoskins
8th June, 2024

How Berberine Boosts Fluconazole to Fight Drug-Resistant Yeast Infections

Clinical isolates of Candida albicans exhibit a range of biofilm-forming capabilities, from low to high (a–c), which allowed for their classification and quantification across 24 strains (d).

Image adapted from: Wu et al. / CC BY (Source)

Key Findings

  • Researchers at Liuzhou People’s Hospital found that combining berberine (BBR) with fluconazole (FLC) significantly inhibited the growth and biofilm formation of FLC-resistant Candida albicans strains
  • The combined treatment downregulated genes responsible for drug resistance and biofilm formation, making the fungal cells more sensitive to fluconazole
  • The addition of berberine reduced cell surface hydrophobicity, further decreasing the ability of Candida albicans to form biofilms
Candida albicans is a common fungal pathogen that can cause a range of infections, from superficial mucous membrane infections to severe systemic infections. The treatment of these infections is complicated by the fungus's ability to form biofilms, which are communities of microorganisms that adhere to surfaces and are inherently resistant to antifungal therapies[2][3]. This resistance poses a significant challenge, particularly for fluconazole (FLC), a widely used antifungal drug. A recent study conducted by researchers at Liuzhou People’s Hospital[1] aimed to address this challenge by investigating the potential of berberine (BBR), a natural compound known for its antimicrobial properties, to enhance the sensitivity of FLC-resistant Candida albicans strains to fluconazole. The study explored the synergistic effects of combining FLC and BBR in overcoming the resistance mechanisms of these strains. The researchers isolated 24 strains of Candida albicans with varying biofilm formation capabilities. They then conducted a series of experiments, including checkerboard, time-kill, and fluorescence microscopy assays, to assess the antifungal effects of FLC alone, BBR alone, and the combination of both. The results demonstrated that the combined treatment of FLC and BBR significantly inhibited the growth and biofilm formation of FLC-resistant Candida albicans strains compared to either treatment alone. One of the key findings of the study was the impact of the combined treatment on gene expression. The researchers found that the combination of FLC and BBR downregulated the expression of efflux pump genes (CDR1 and MDR), which are known to contribute to drug resistance by actively pumping antifungal agents out of the fungal cells. Additionally, the expression of the hyphal gene HWP1 and the adhesion gene ALS3 was also downregulated, which are important for biofilm formation and virulence. Conversely, the transcriptional repressor gene TUP1 was upregulated, indicating a suppression of virulence factors. Furthermore, the addition of BBR led to a significant reduction in cell surface hydrophobicity, which is a characteristic that facilitates biofilm formation and adhesion to surfaces. This reduction in hydrophobicity likely contributed to the decreased biofilm formation observed in the combined treatment group. To delve deeper into the mechanisms behind these effects, the researchers performed genome-wide sequencing analysis to identify resistance-related genes and virulence factors. They discovered that the combination treatment influenced several metabolic pathways, particularly those involved in amino acid and carbon metabolism. Notably, the expression of several ergosterol (ERG) genes, which are involved in the synthesis of cell membrane sterols and are related to drug resistance, was altered. Specifically, the combination treatment upregulated the expression of ERG1, ERG3, ERG4, ERG5, ERG24, and ERG25 genes, while downregulating ERG6 and ERG9 genes compared to fluconazole treatment alone. These findings are significant as they provide a comprehensive understanding of how berberine enhances the effectiveness of fluconazole against resistant Candida albicans strains. By targeting multiple resistance mechanisms and virulence factors, the combined treatment offers a promising strategy to overcome the limitations of current antifungal therapies. The study builds on previous research that highlighted the challenges posed by biofilm formation in Candida albicans and the limitations of existing antifungal treatments[3]. It also aligns with the evolving epidemiology of Candida infections, where non-albicans species and multidrug-resistant strains are becoming more prevalent, necessitating new and effective treatment options[4]. In conclusion, the study by Liuzhou People’s Hospital provides valuable insights into the potential of combining fluconazole with berberine to treat FLC-resistant Candida albicans infections. By elucidating the underlying mechanisms of this synergistic effect, the research offers a promising avenue for enhancing the efficacy of antifungal therapies and addressing the growing challenge of drug-resistant fungal infections.

MedicineBiotechBiochem

References

Main Study

1) Mechanism and bioinformatics analysis of the effect of berberine-enhanced fluconazole against drug-resistant Candida albicans

Published 7th June, 2024

https://doi.org/10.1186/s12866-024-03334-0

Related Studies

2) Candida albicans and candidalysin in inflammatory disorders and cancer.

https://doi.org/10.1111/imm.13255

3) Biofilm of Candida albicans: formation, regulation and resistance.

https://doi.org/10.1111/jam.14949

4) Invasive candidiasis: investigational drugs in the clinical development pipeline and mechanisms of action.

https://doi.org/10.1080/13543784.2022.2086120


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