Work

Berberine-fluconazole synergy against drug-resistant Candida albicans: association with disruption of the Ire1-mediated UPR pathway

Year: 2026

Type: article

Abstract: Purpose Candida albicans -mediated invasive candidiasis has high mortality. Novel strategies against azole resistance and biofilm-associated infections are clinically urgently needed. This study aimed to explore the synergistic antifungal and antibiofilm effects of berberine (BBH) combined with fluconazole (FCZ) against drug-resistant C. albicans , and to elucidate the underlying molecular mechanisms. Methods The synergistic effect was assessed using fractional inhibitory concentration index and time-kill curve assays. BBH cytotoxicity was evaluated via CCK-8 assay. Biofilm formation was observed through crystal violet staining and Spider plate culture. Transcriptome sequencing was performed to screen potential drug targets. Endoplasmic reticulum (ER) homeostasis was evaluated by assessing stress sensitivity, observing ultrastructure, quantifying misfolded proteins, and measuring secreted protease activity. HAC1 splicing analysis and detection of unfolded protein response (UPR)-related gene expression were applied to verify perturbation of the UPR pathway. Autophagy activation was determined by transmission electron microscopy, vacuole staining, autophagy inhibitor intervention, and detection of autophagy-related genes and the Atg1 protein. Results BBH combined with FCZ exerted significant synergistic activity and biofilm inhibition. Such synergism depended on dysfunction of the ER stress-regulating UPR pathway. Combined treatment inhibited UPR activation and disrupted ER homeostasis, as manifested by ER dilation, misfolded protein accumulation and reduced secreted protease activity. High-dose combination induced excessive autophagy, thereby triggering vacuolar rupture and C. albicans cell death. Conclusion The BBH-FCZ combination produced prominent synergism and antibiofilm effects against drug-resistant C. albicans . This work provided new insights into targeting the ER stress regulatory pathway to manage azole-resistant fungal infections.

Source: Frontiers in Microbiology

DOI: 10.3389/fmicb.2026.1965937

Authors: Daifan Yue, Dongming Zheng, Zhen Song, Dongmei Li, Yan Li

Institution: Chengdu University of Traditional Chinese Medicine

Language: English

Topic: Antifungal resistance and susceptibility

Subfield: Infectious Diseases

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801