Candida glabrata is an important human fungal pathogen known to trigger serious infections in immune-compromised individuals. Its ability to form biofilms, which exhibit high tolerance to antifungal treatments, has been considered as an important virulence factor. However, the mechanisms involving antifungal resistance in biofilms and the impact of host niche environments on these processes are still poorly defined. In this study, we performed a whole-transcriptome analysis of C. glabrata biofilm cells exposed to different environmental conditions and constraints in order to identify the molecular pathways involved in fluconazole resistance and understand how acidic pH niches, associated with the presence of acetic acid, are able to modulate these responses. We show that fluconazole treatment induces gene expression reprogramming in a carbon source and pH-dependent manner. This is particularly relevant for a set of genes involved in DNA replication, ergosterol, and ubiquinone biosynthesis. We also provide additional evidence that the loss of mitochondrial function is associated with fluconazole resistance, independently of the growth condition. Lastly, we propose that C. glabrata Mge1, a cochaperone involved in iron metabolism and protein import into the mitochondria, is a key regulator of fluconazole susceptibility during carbon and pH adaptation by reducing the metabolic flux towards toxic sterol formation. These new findings suggest that different host microenvironments influence directly the physiology of C. glabrata, with implications on how this pathogen responds to antifungal treatment. Our analyses identify several pathways that can be targeted and will potentially prove to be useful for developing new antifungals to treat biofilm-based infections.

中文翻译：

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碳源调节了光滑念珠菌生物膜细胞对氟康唑的转录反应。

光滑念珠菌是一种重要的人类真菌病原体，已知会在免疫受损的个体中引发严重感染。它形成生物膜的能力被证明是重要的毒力因子，该生物膜对抗真菌治疗具有很高的耐受性。但是，涉及生物膜抗真菌性的机制以及宿主生态位环境对这些过程的影响仍然不清楚。在这项研究中，我们对暴露于不同环境条件和限制条件下的毛毛衣藻生物膜细胞进行了全转录组分析，以鉴定参与氟康唑耐药性的分子途径，并了解酸性pH壁how与乙酸的存在如何相关，能够调节这些反应。我们显示氟康唑治疗诱导碳源和pH依赖方式的基因表达重编程。这与涉及DNA复制，麦角固醇和泛醌生物合成的一组基因特别相关。我们还提供了其他证据，表明线粒体功能的丧失与氟康唑耐药性有关，而与生长条件无关。最后，我们提出，C。glabrata Mge1，参与铁代谢和线粒体蛋白质进口的陪伴酮，是通过减少代谢通向有毒甾醇的通量来调节碳和pH值期间氟康唑敏感性的关键调节剂。这些新发现表明，不同的宿主微环境直接影响光滑念珠菌的生理，并对该病原体对抗真菌治疗的反应产生影响。