白色念珠菌
伊曲康唑
白色体
药物重新定位
药理学
伏立康唑
微生物学
生物
联合疗法
抗真菌药
抗药性
两性霉素B
药品
医学
抗真菌
作者
Tianyu Chen,Jing Yao,K Quan,Jingchen Xu,Xudong Hang,Qian Tong,Genyan Liu,Peipei Luo,Liping Zeng,Ganzhu Feng,Hongkai Bi
摘要
Opportunistic fungal infections, particularly caused by Candida albicans, remain a common cause of high morbidity and mortality in immunocompromised patients. The escalating prevalence of antifungal drug resistance necessitates the immediate exploration of alternative treatment strategies to combat these life-threatening fungal diseases. In this study, we investigated the antifungal efficacy of firsocostat, a human acetyl-CoA carboxylase (ACC) inhibitor, against C. albicans. Firsocostat alone displayed moderate antifungal activity, while combining it with voriconazole, itraconazole, or amphotericin B exhibited synergistic effects across almost all drug-sensitive and drug-resistant C. albicans strains tested. These observed synergies were further validated in two mouse models of oropharyngeal and systemic candidiasis, where the combination therapies demonstrated superior fungicidal effects compared to monotherapy. Moreover, firsocostat was shown to directly bind to C. albicans ACC and inhibit its enzymatic activity. Sequencing spontaneous firsocostat-resistant mutants revealed mutations mapping to C. albicans ACC, confirming that firsocostat has retained its target in C. albicans. Overall, our findings suggest that repurposing firsocostat, either alone or in combination with other antifungal agents, holds promising potential in the development of antifungal drugs and the treatment of candidiasis.
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