ABSTRACT

Objectives

The resistance of Candida albicans (C. albicans) to classical antifungals has been increasing significantly and poses great challenges to clinical treatment. The objective of this research is to evaluate whether the combination of lonidamine (LND) and fluconazole (FLC) have synergistic antifungal activity against C. albicans and to explore the underlying synergistic mechanisms against FLC-resistant C. albicans.

Methods

The antifungal effect on resistant planktonic C. albicans and preformed biofilms were performed by broth microdilution assay and XTT reduction assay. The influence on hyphal growth, cellular ROS level, metacaspase activity and drug transporters were investigated by morphogenesis observation, DCFH-DA, FITC-VAD-FMK and rhodamine6G assay, respectively.

Results

LND in combination with FLC exhibited synergistic antifungal effects against resistant planktonic C. albicans and preformed biofilms of C. albicans in the early stages (performed at 4 h and 8 h). The synergistic mechanisms associated with the inhibition of the hyphal growth and the activation of metacaspase, but were not related to mediate cellular ROS level or drug uptake and efflux in resistant C. albicans.

Conclusion

LND combined with FLC exhibited synergistic antifungal activity against resistant C. albicans, and the synergistic mechanisms were related to anti-biofilms and reduce virulence factors.

Expert opinion

The emergence of fluconazole-resistant Candida albicans strains poses great challenges to clinical treatment. Drug combination of non-antifungals and fluconazole has attracted a lot of attention to overcome Candida albicans drug resistance.

中文翻译：

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氯尼达明联合氟康唑对白色念珠菌的抗真菌作用和潜在机制。

摘要

目标

白色念珠菌（C. albicans）对经典抗真菌药物的耐药性显着增加，对临床治疗提出了巨大挑战。本研究的目的是评估氯尼达明 (LND) 和氟康唑 (FLC) 的组合是否对白色念珠菌具有协同抗真菌活性，并探索对 FLC 抗性白色念珠菌的潜在协同机制。

方法

通过肉汤微量稀释试验和 XTT 还原试验对抗性浮游白色念珠菌和预形成的生物膜进行抗真菌作用。分别通过形态发生观察、DCFH-DA、FITC-VAD-FMK和罗丹明6G试验研究了对菌丝生长、细胞ROS水平、metacaspase活性和药物转运蛋白的影响。

结果

LND 与 FLC 组合在早期阶段（在 4 小时和 8 小时进行）对抗性浮游白色念珠菌和预先形成的白色念珠菌生物膜表现出协同抗真菌作用。协同机制与抑制菌丝生长和活化 metacaspase 相关，但与介导细胞 ROS 水平或耐药性白色念珠菌的药物摄取和流出无关。

结论

LND联合FLC对耐药性白色念珠菌表现出协同抗真菌活性，协同机制与抗生物膜和降低毒力因子有关。

专家意见

耐氟康唑白色念珠菌菌株的出现对临床治疗提出了巨大挑战。非抗真菌药物与氟康唑的药物联用在克服白色念珠菌耐药性方面备受关注。