Department of Laboratory Medicine, Key Laboratory of Precision Medicine for Viral Diseases, Guangxi Health Commission Key Laboratory of Clinical Biotechnology, Liuzhou People's Hospital, Liu Zhou, 545006, China.
Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, The General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China.
BMC Microbiol. 2024 Jun 7;24(1):196. doi: 10.1186/s12866-024-03334-0.
Biofilms produced by Candida albicans present a challenge in treatment with antifungal drug. Enhancing the sensitivity to fluconazole (FLC) is a reasonable method for treating FLC-resistant species. Moreover, several lines of evidence have demonstrated that berberine (BBR) can have antimicrobial effects. The aim of this study was to clarify the underlying mechanism of these effects. We conducted a comparative study of the inhibition of FLC-resistant strain growth by FLC treatment alone, BBR treatment alone, and the synergistic effect of combined FLC and BBR treatment. Twenty-four isolated strains showed distinct biofilm formation capabilities. The antifungal effect of combined FLC and BBR treatment in terms of the growth and biofilm formation of Candida albicans species was determined via checkerboard, time-kill, and fluorescence microscopy assays. The synergistic effect of BBR and FLC downregulated the expression of the efflux pump genes CDR1 and MDR, the hyphal gene HWP1, and the adhesion gene ALS3; however, the gene expression of the transcriptional repressor TUP1 was upregulated following treatment with this drug combination. Furthermore, the addition of BBR led to a marked reduction in cell surface hydrophobicity. To identify resistance-related genes and virulence factors through genome-wide sequencing analysis, we investigated the inhibition of related resistance gene expression by the combination of BBR and FLC, as well as the associated signaling pathways and metabolic pathways. The KEGG metabolic map showed that the metabolic genes in this strain are mainly involved in amino acid and carbon metabolism. The metabolic pathway map showed that several ergosterol (ERG) genes were involved in the synthesis of cell membrane sterols, which may be related to drug resistance. In this study, BBR + FLC combination treatment upregulated the expression of the ERG1, ERG3, ERG4, ERG5, ERG24, and ERG25 genes and downregulated the expression of the ERG6 and ERG9 genes compared with fluconazole treatment alone (p < 0.05).
白色念珠菌生物膜的产生给抗真菌药物治疗带来了挑战。提高对氟康唑（FLC）的敏感性是治疗 FLC 耐药物种的合理方法。此外，有几条证据表明小檗碱（BBR）具有抗菌作用。本研究旨在阐明这些作用的潜在机制。我们对单独使用 FLC 治疗、单独使用 BBR 治疗以及联合使用 FLC 和 BBR 治疗对 FLC 耐药株生长的抑制作用进行了比较研究。24 株分离株表现出明显的生物膜形成能力。通过棋盘试验、时间杀伤试验和荧光显微镜试验，确定了联合使用 FLC 和 BBR 治疗对白色念珠菌生物膜形成和生长的抗真菌作用。BBR 和 FLC 的协同作用下调了外排泵基因 CDR1 和 MDR、菌丝基因 HWP1 和粘附基因 ALS3 的表达，但药物联合使用后转录阻遏物 TUP1 的基因表达上调。此外，添加 BBR 导致细胞表面疏水性显著降低。通过全基因组测序分析，我们研究了 BBR 和 FLC 联合使用对相关耐药基因表达的抑制作用，以及相关信号通路和代谢通路。KEGG 代谢图谱显示，该菌株的代谢基因主要参与氨基酸和碳代谢。代谢途径图谱显示，几种麦角固醇（ERG）基因参与细胞膜固醇的合成，这可能与耐药性有关。在这项研究中，与单独使用氟康唑相比，BBR + FLC 联合治疗上调了 ERG1、ERG3、ERG4、ERG5、ERG24 和 ERG25 基因的表达，下调了 ERG6 和 ERG9 基因的表达（p < 0.05）。
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