Repurposing the antispasmodic drug pinaverium bromide as a novel antifungal agent and synergist against Candida albicans

Fungal infections represent a significant and growing threat to public health, exacerbated by an expanding population of immunocompromised individuals and the increasing prevalence of resistance to conventional antifungal agents. Drug repurposing offers a strategic and efficient pathway for antifungal discovery, leveraging existing pharmacotherapies to reduce development costs and mitigate safety risks. This study evaluated the antifungal potential of pinaverium bromide, an FDA-approved antispasmodic drug for functional gastrointestinal disorders, against the prevalent pathogen Candida albicans. Our in vitro analyses revealed that pinaverium bromide demonstrated standalone antifungal activity and acted synergistically with amphotericin B or azole drugs. Moreover, it effectively attenuated key virulence factors of C. albicans, including hyphal formation and biofilm development. The therapeutic efficacy of both monotherapy and combination therapy with amphotericin B or voriconazole was validated in two murine models of systemic candidiasis. Mechanistically, pinaverium bromide disrupted mitochondrial function, induced apoptotic cell death, and impaired iron homeostasis in C. albicans. When combined with amphotericin B, it potentiated the drug’s effect by amplifying reactive oxygen species accumulation and enhancing membrane permeabilization. These findings support the potential of pinaverium bromide as a novel antifungal agent, either when used alone or in combination with established antifungal therapies.

真菌感染对公共卫生构成了日益严峻的重大威胁，免疫功能低下人群规模的持续扩大以及传统抗真菌药物耐药性发生率的不断攀升，进一步加剧了这一公共卫生危机。药物重定位（drug repurposing）为抗真菌药物研发提供了兼具策略性与高效性的可行路径：通过利用已获批的药物疗法，可有效降低研发成本并规避安全风险。本研究针对临床常见致病菌白色念珠菌（Candida albicans），评估了匹维溴铵（pinaverium bromide）的抗真菌潜力——匹维溴铵是一款获美国食品药品监督管理局（FDA）批准的解痉药物，用于治疗功能性胃肠疾病。体外实验分析结果显示，匹维溴铵不仅展现出单一用药的抗真菌活性，还可与两性霉素B（amphotericin B）或唑类抗真菌药物产生协同作用。此外，该药物可有效削弱白色念珠菌的关键毒力因子，包括菌丝形成与生物膜生成。在两种全身性念珠菌病小鼠模型中，研究验证了匹维溴铵单药疗法，以及与两性霉素B或伏立康唑（voriconazole）联合疗法的治疗效果。从作用机制来看，匹维溴铵可破坏白色念珠菌的线粒体功能、诱导细胞凋亡，并损伤其铁稳态；当与两性霉素B联用时，其可通过促进活性氧（reactive oxygen species）积累与增强细胞膜通透性，强化两性霉素B的抗菌效果。上述研究结果证实，匹维溴铵具备开发为新型抗真菌药物的潜力，既可单独使用，也可与现有标准抗真菌疗法联合应用。