Ire1 inhibitors attenuate Candida albicans pathogenicity and demonstrate potential for application in antifungal therapy

Hua Wang¹Mengyan Li²Qiuyue Wang¹Huihai Zhao¹Jiang Mengyu¹Qi Cui¹Daxin Lei¹Keran Jia^1*Fukun Wang^1*

• ¹Bethune International Peace Hospital Library, Shijiazhuang, China
• ²The First Hospital of Hebei Medical University, Shijiazhuang, China

Candida albicans is a prevalent opportunistic pathogen that can cause both superficial and invasive infections. The unfolded protein response (UPR) pathway, triggered by endoplasmic reticulum stress, is crucial for Candida albicans survival and pathogenicity. Among the UPR components, Ire1 plays a key role in regulating this stress response. In this study, we explored the therapeutic potential of Ire1 inhibitors, specifically targeting its RNase activity, on Candida albicans pathogenicity. Using molecular docking, we identified three small-molecule inhibitors—MKC8866, STF083010, and 4μ8c—that exhibited strong binding affinities to the Ire1 protein. The inhibitor 4μ8c was found to significantly impair key pathogenic traits, including morphological transformation, adhesion, flocculation, and biofilm formation. Additionally, it enhanced the susceptibility of Candida albicans to antifungal drugs and reduced the expression of virulence-related genes. In vivo studies using a murine intestinal colonization model demonstrated that 4μ8c effectively reduced fungal colonization and intestinal tissue damage caused by Candida albicans. This study demonstrates the pharmacological inhibition of the unfolded protein response signaling pathway in Candida albicans is feasible. 4μ8c can serve as a potential antifungal agent that diminishes the adaptability of Candida albicans to environmental stress and its pathogenicity.