The incidence of infections by non-albicans Candida species, including Candida krusei, is increasing. Candida krusei exhibits intrinsic resistance to fluconazole and rapidly develops acquired resistance to other antifungals. Moreover, this yeast can form biofilm with increased resistance. Hence, there is a need to develop novel therapeutic strategies to combat infections caused by this pathogen. One such approach is through combination therapy with natural compounds, such as polyunsaturated fatty acids (PUFAs). This study aims to investigate the effect of PUFAs on fluconazole susceptibility of C. krusei biofilms, as well as the conserved nature of these effects in the Caenorhabditis elegans infection model. C. krusei biofilms were exposed to various fatty acids as well as combinations of fluconazole and linoleic acid (LA) or gamma-linolenic acid (GLA). The effect of these treatments on biofilm formation, cell ultrastructure, membrane integrity, oxidative stress and efflux pump activity was evaluated. In addition, the ability of the PUFAs to prolong survival and reduce the fungal burden of infected C. elegans, in the absence and presence of fluconazole, was assessed. Two PUFAs, LA and GLA had displayed significant inhibition of C. krusei biofilms and both of them increased the susceptibility of C. krusei biofilm to fluconazole in vitro via induction of oxidative stress, cell membrane damage, and disruption of efflux pump activity. These PUFAs also extended the lifespan of infected nematodes and displayed a potentiating effect with fluconazole in this model. This may pave the way for future studies into novel antifungal drug targets and treatment options. Lay summary The pathogenic yeast, Candida krusei, is naturally resistant to the antifungal drug, fluconazole. This study finds that polyunsaturated fatty acids, linoleic and gamma-linolenic acid, can inhibit C. krusei and overcome this resistance of in vitro biofilms, as well as in a nematode infection model.

中文翻译：

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多不饱和脂肪酸单独或与氟康唑联合对体外和秀丽隐杆线虫的克氏念珠菌生物膜的抑制作用

包括克氏假丝酵母在内的非白色念珠菌感染的发生率正在增加。Candida krusei 表现出对氟康唑的内在抗性，并迅速发展出对其他抗真菌剂的获得性抗性。此外，这种酵母可以形成具有增强抵抗力的生物膜。因此，需要开发新的治疗策略来对抗由这种病原体引起的感染。一种这样的方法是通过与天然化合物如多不饱和脂肪酸 (PUFA) 的联合治疗。本研究旨在研究多不饱和脂肪酸对克氏梭菌生物膜氟康唑敏感性的影响，以及这些影响在秀丽隐杆线虫感染模型中的保守性。C。krusei 生物膜暴露于各种脂肪酸以及氟康唑和亚油酸 (LA) 或 γ-亚麻酸 (GLA) 的组合。评估了这些处理对生物膜形成、细胞超微结构、膜完整性、氧化应激和外排泵活性的影响。此外，评估了在氟康唑不存在和存在的情况下，PUFA 延长存活期和减少感染的秀丽隐杆线虫的真菌负担的能力。两种 PUFA，LA 和 GLA 对克氏梭菌生物膜具有显着抑制作用，并且它们都通过诱导氧化应激、细胞膜损伤和破坏外排泵活性，增加了克氏梭菌生物膜对氟康唑的敏感性。这些多不饱和脂肪酸还延长了受感染线虫的寿命，并在该模型中显示出与氟康唑的增强作用。这可能为未来研究新的抗真菌药物靶点和治疗方案铺平道路。总结 致病酵母，克氏念珠菌，对抗真菌药物氟康唑具有天然抗药性。本研究发现，多不饱和脂肪酸、亚油酸和 γ-亚麻酸可以抑制克氏梭菌并克服体外生物膜以及线虫感染模型的这种抗性。