Atractylodin Enhances the Efficacy of Fluconazole Against Fluconazole-Resistant C. albicans by Promoting ROS Accumulation and Synergizes with Fluconazole Against C. albicans Biofilm.
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引用次数: 0
Abstract
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.
期刊介绍：
Mycopathologia is an official journal of the International Union of Microbiological Societies (IUMS). Mycopathologia was founded in 1938 with the mission to ‘diffuse the understanding of fungal diseases in man and animals among mycologists’. Many of the milestones discoveries in the field of medical mycology have been communicated through the pages of this journal. Mycopathologia covers a diverse, interdisciplinary range of topics that is unique in breadth and depth. The journal publishes peer-reviewed, original articles highlighting important developments concerning medically important fungi and fungal diseases. The journal highlights important developments in fungal systematics and taxonomy, laboratory diagnosis of fungal infections, antifungal drugs, clinical presentation and treatment, and epidemiology of fungal diseases globally. Timely opinion articles, mini-reviews, and other communications are usually invited at the discretion of the editorial board. Unique case reports highlighting unprecedented progress in the diagnosis and treatment of fungal infections, are published in every issue of the journal. MycopathologiaIMAGE is another regular feature for a brief clinical report of potential interest to a mixed audience of physicians and laboratory scientists. MycopathologiaGENOME is designed for the rapid publication of new genomes of human and animal pathogenic fungi using a checklist-based, standardized format.
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