Proteomic Analysis Reveals a Synergistic Mechanism of Fluconazole and Berberine against Fluconazole-Resistant Candida albicans: Endogenous ROS Augmentation

• Published in: Journal of proteome research Vol. 8; no. 11; pp. 5296 - 5304
• Main Authors: Xu, Yi, Wang, Yan, Yan, Lan, Liang, Rong-Mei, Dai, Bao-Di, Tang, Ren-Jie, Gao, Ping-Hui, Jiang, Yuan-Ying
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 06.11.2009
• Subjects: Adenosine Triphosphate - metabolism; Antifungal Agents - pharmacology; Antioxidants - metabolism; Ascorbic Acid - metabolism; Berberine - pharmacology; Candida albicans - drug effects; Candida albicans - physiology; Cell Respiration - physiology; Drug Resistance, Fungal - physiology; Drug Synergism; Fluconazole - pharmacology; Fungal Proteins - genetics; Fungal Proteins - metabolism; Humans; Membrane Potential, Mitochondrial - physiology; Microbial Sensitivity Tests; Proteome - analysis; Reactive Oxygen Species - metabolism; Candida albicans; proteomics; synergistic mechanism; fluconazole resistance; berberine
• ISSN: 1535-3893; 1535-3907
• DOI: 10.1021/pr9005074

Our previous study showed that concomitant use of berberine (BBR) and fluconazole (FLC) provided a synergistic action against FLC-resistant Candida albicans (C. albicans) clinical strains in vitro. To clarify the mechanism underlying this action, we performed a comparative proteomic study in untreated control cells and cells treated with FLC and/or BBR in 2 clinical strains of C. albicans resistant to FLC. Our analyses identified 16 differentially expressed proteins, most of which were related to energy metabolisms (e.g., Gap1, Adh1, and Aco1). Functional analyses revealed that FLC + BBR treatment increased mitochondrial membrane potential, decreased intracellular ATP level, inhibited ATP-synthase activity, and increased generation of endogenous reactive oxygen species (ROS) in FLC-resistant strains. In addition, checkerboard microdilution assay showed that addition of antioxidant ascorbic acid or reduced glutathione reduced the synergistic antifungal activity of FLC + BBR significantly. These results suggest that mitochondrial aerobic respiration shift and endogenous ROS augmentation contribute to the synergistic action of FLC + BBR against FLC-resistant C. albicans.