Li Yiman, Jiao Ping, Li Yuanyuan, Gong Ying, Chen Xueqi, Sun Shujuan
Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
School of Pharmaceutical Sciences, Shandong University, Jinan, China.
Front Microbiol. 2019 Dec 18;10:2853. doi: 10.3389/fmicb.2019.02853. eCollection 2019.
Over the last few decades, candidiasis has exhibited an increasing incidence worldwide, causing high mortality in immunocompromised patients. is one of the leading opportunistic fungal pathogens. However, due to the increased use of antifungal agents, resistance of to conventional agents, especially fluconazole, has frequently emerged. Therefore, research on the use of combinations of current drugs to sensitize antifungal agents and overcome fungal resistance has attracted considerable attention. This study demonstrated for the first time that D-penicillamine (PCA) combined with fluconazole showed a synergistic effect against . PCA combined with fluconazole not only showed synergistic effects against planktonic cells of , but also showed synergistic effects against biofilms formed within 12 h . In addition, a infection model was used to evaluate the effects of this drug combination. The results showed that the combination of the two drugs could improve the survival rate, decrease the fungal burden, and reduce the tissue invasion of larvae. Finally, we explored the potential synergistic mechanisms of the drug combination, mainly including inhibition of the morphological transformation, reduction of the intracellular calcium concentration, and the activation of metacaspase, which is closely related to cell apoptosis. These findings might provide novel insights into antifungal drug discovery and the treatment of candidiasis caused by .
在过去几十年中，念珠菌病在全球范围内的发病率呈上升趋势，在免疫功能低下的患者中导致高死亡率。念珠菌是主要的机会性真菌病原体之一。然而，由于抗真菌药物的使用增加，念珠菌对传统药物，尤其是氟康唑的耐药性频繁出现。因此，关于使用现有药物组合来使抗真菌药物敏感并克服真菌耐药性的研究引起了相当大的关注。本研究首次证明，D-青霉胺（PCA）与氟康唑联合使用对念珠菌具有协同作用。PCA与氟康唑联合使用不仅对念珠菌的浮游细胞显示出协同作用，而且对12小时内形成的念珠菌生物膜也显示出协同作用。此外，使用念珠菌感染模型来评估这种药物组合的效果。结果表明，两种药物的组合可以提高存活率，降低真菌负荷，并减少念珠菌幼虫的组织侵袭。最后，我们探讨了药物组合的潜在协同机制，主要包括抑制形态转化、降低细胞内钙浓度以及激活与细胞凋亡密切相关的metacaspase。这些发现可能为抗真菌药物的发现以及由念珠菌引起的念珠菌病的治疗提供新的见解。
