Candida auris is an emerging multidrug-resistant human fungal pathogen refractory to treatment by several classes of antifungal drugs. Unlike other Candida species, C. auris can adhere to human skin for prolonged periods of time, allowing for efficient skin-to-skin transmission in the hospital environments. However, molecular mechanisms underlying pronounced multidrug resistance and adhesion traits are poorly understood. Two-component signal transduction and mitogen-activated protein (MAP) kinase signaling are important regulators of adherence, antifungal drug resistance, and virulence. Here, we report that genetic removal of SSK1 encoding a response regulator and the mitogen-associated protein kinase HOG1 restores the susceptibility to both amphotericin B (AMB) and caspofungin (CAS) in C. auris clinical strains. The loss of SSK1 and HOG1 alters membrane lipid permeability, cell wall mannan content, and hyperresistance to cell wall-perturbing agents. Interestingly, our data reveal variable functions of SSK1 and HOG1 in different C. auris clinical isolates, suggesting a pronounced genetic plasticity affecting cell wall function, stress adaptation, and multidrug resistance. Taken together, our data suggest that targeting two-component signal transduction systems could be suitable for restoring C. auris susceptibility to antifungal drugs.

中文翻译：

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双组分反应调节剂 Ssk1 和丝裂原活化蛋白激酶 Hog1 控制念珠菌的抗真菌药物耐药性和细胞壁结构

念珠菌是一种新兴的耐多药人类真菌病原体，对几类抗真菌药物的治疗无效。与其他念珠菌不同，耳念珠菌可以长时间粘附在人体皮肤上，从而在医院环境中进行有效的皮肤对皮肤传播。然而，人们对显着的多药耐药性和粘附特性的分子机制知之甚少。双组分信号转导和丝裂原活化蛋白 (MAP) 激酶信号传导是依从性、抗真菌药物耐药性和毒力的重要调节器。在这里，我们报告了SSK1编码反应调节器和丝裂原相关蛋白激酶HOG1 的基因去除在耳念珠菌临床菌株中恢复对两性霉素 B (AMB) 和卡泊芬净 (CAS) 的敏感性。的损失SSK1和HOG1涂改膜脂渗透性，细胞壁甘露聚糖含量，和hyperresistance到细胞壁扰动剂。有趣的是，我们的数据揭示了SSK1和HOG1在不同的耳念珠菌临床分离株中的可变功能，表明影响细胞壁功能、应激适应和多药耐药性的显着遗传可塑性。综上所述，我们的数据表明，靶向双组分信号转导系统可能适合恢复耳念珠菌对抗真菌药物的敏感性。