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<p>The rise of resistant <i>Candida albicans</i> (<i>C. albicans</i>) poses a significant challenge to fluconazole (FCZ) therapy. Restoring FCZ sensitivity offers a therapeutic strategy for resistant isolates. Atractylodin (ATL), a polyacetylene from&#xa0;<i>Atractylodis Rhizoma</i>, possesses antifungal activity. This study aimed to investigate the synergistic efficacy of ATL and FCZ against drug-resistant <i>C. albicans</i> and explore the underlying mechanisms. Fractional inhibitory concentration index (FICI) for synergy evaluation, scanning electron microscopy, and reactive oxygen species (ROS) production were conducted to investigate the antifungal effect on FCZ-resistant <i>C. albicans</i> 04<i>.</i> Transcriptome sequencing was performed to confirm the differentially expressed genes between ATL + FCZ and FCZ treatment. Meanwhile, the effect of ATL and FCZ combination on the virulence factors was explored through hyphae formation and antibiofilm experiment. Microbial metabolomics was used to identify the mechanism of the synergistic biofilm inhibition. ATL had significant synergistic effect with FCZ against FCZ-resistant <i>C. albicans</i>, and reduced the MICs of FCZ by 32 or 64 times, with FICI &lt; 0.5. The ATL and FCZ combination caused damage to <i>C. albicans</i> cells and significantly increased ROS levels. Transcriptome sequencing also revealed that the gene involved in ROS inculding SOD2 and HSP90 were upregulated, while cell wall-related genes CHS7 and CWH8 were downregulated. Meanwhile, ATL strongly synergized with FCZ against hyphae and biofilm formation of FCZ resistant <i>C. albicans</i>. Metabolomics revealed that key metabolites (e.g., glucose 6-phosphate, isocitric acid, most lipid species, leucylproline, 3'-adenylic acid) were significantly downregulated in the ATL + FCZ combination group versus control and monotherapies. In conclusion, we demonstrated for the first time that the combination of ATL and FCZ may produce a synergistic antifungal effect against FCZ-resistant&#xa0;<i>C. albicans</i>, potentially through the induction of ROS accumulation. The alterations of metabolites mainly involved in glycolysis, TCA cycle, amino acids, lipid, and nucleotide metabolism may be responsible for the inhibition of <i>C. albicans</i> biofilm formation. ATL exhibited a strong synergist with FCZ against <i>C. albicans</i>, highlighting the potential of ATL as a sensitizer in clinical antifungal therapy.</p>

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Atractylodin Enhances the Efficacy of Fluconazole Against Fluconazole-Resistant C. albicans by Promoting ROS Accumulation and Synergizes with Fluconazole Against C. albicans Biofilm

  • 期刊论文

  • 发表日期：

    2026年4月2日

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  • Jinyun Song,
  • Juan Wang,
  • Sijia Hu,
  • Jinghan Gao,
  • Zihao Liang,
  • Shanzhong Tan,
  • Hongyu Zhao

摘要

The rise of resistant Candida albicans (C. albicans) poses a significant challenge to fluconazole (FCZ) therapy. Restoring FCZ sensitivity offers a therapeutic strategy for resistant isolates. Atractylodin (ATL), a polyacetylene from Atractylodis Rhizoma, possesses antifungal activity. This study aimed to investigate the synergistic efficacy of ATL and FCZ against drug-resistant C. albicans and explore the underlying mechanisms. Fractional inhibitory concentration index (FICI) for synergy evaluation, scanning electron microscopy, and reactive oxygen species (ROS) production were conducted to investigate the antifungal effect on FCZ-resistant C. albicans 04. Transcriptome sequencing was performed to confirm the differentially expressed genes between ATL + FCZ and FCZ treatment. Meanwhile, the effect of ATL and FCZ combination on the virulence factors was explored through hyphae formation and antibiofilm experiment. Microbial metabolomics was used to identify the mechanism of the synergistic biofilm inhibition. ATL had significant synergistic effect with FCZ against FCZ-resistant C. albicans, and reduced the MICs of FCZ by 32 or 64 times, with FICI < 0.5. The ATL and FCZ combination caused damage to C. albicans cells and significantly increased ROS levels. Transcriptome sequencing also revealed that the gene involved in ROS inculding SOD2 and HSP90 were upregulated, while cell wall-related genes CHS7 and CWH8 were downregulated. Meanwhile, ATL strongly synergized with FCZ against hyphae and biofilm formation of FCZ resistant C. albicans. Metabolomics revealed that key metabolites (e.g., glucose 6-phosphate, isocitric acid, most lipid species, leucylproline, 3'-adenylic acid) were significantly downregulated in the ATL + FCZ combination group versus control and monotherapies. In conclusion, we demonstrated for the first time that the combination of ATL and FCZ may produce a synergistic antifungal effect against FCZ-resistant C. albicans, potentially through the induction of ROS accumulation. The alterations of metabolites mainly involved in glycolysis, TCA cycle, amino acids, lipid, and nucleotide metabolism may be responsible for the inhibition of C. albicans biofilm formation. ATL exhibited a strong synergist with FCZ against C. albicans, highlighting the potential of ATL as a sensitizer in clinical antifungal therapy.