The Two-Component Response Regulator Ssk1 and the Mitogen-Activated Protein Kinase Hog1 Control Antifungal Drug Resistance and Cell Wall Architecture of Candida auris.
The Two-Component Response Regulator Ssk1 and the Mitogen-Activated Protein Kinase Hog1 Control Antifungal Drug Resistance and Cell Wall Architecture of Candida auris.
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双组分反应调节因子Ssk1和丝裂原活化蛋白激酶Hog1控制耳念珠菌的抗真菌药物耐药性和细胞壁结构
DOI：
10.1128/msphere.00973-20
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发表时间：
2020-10-14
期刊：
影响因子：
4.8
通讯作者：
Chauhan N
中科院分区：
文献类型：
--
作者：
Shivarathri R;Jenull S;Stoiber A;Chauhan M;Mazumdar R;Singh A;Nogueira F;Kuchler K;Chowdhary A;Chauhan N
耳念珠菌是一种新兴的耐多药真菌病原体，对人类健康构成严重的全球性威胁。美国疾病控制与预防中心（CDC）已将金黄色葡萄球菌列为未来十年对公众健康的紧急威胁，因为它具有重大的临床和经济影响，缺乏有效的抗真菌药物，而且未来还会出现新的金黄色葡萄球菌感染。重要的是，全球抗菌素耐药性监测系统（GLASS）强调需要更强大和有效的全球监测计划，以便识别和监测念珠菌感染的抗真菌耐药性。尽管耳念珠菌感染具有临床意义，但我们对其病理生理学和毒力、对人类免疫监测的反应以及多种抗真菌耐药性的分子基础的全面了解仍处于起步阶段。在这里，我们展示了金黄色葡萄球菌临床分离株的显著表型可塑性。此外，我们证明了应激反应机制在调节多药耐药中的关键作用，并表明细胞壁结构和组成是决定抗真菌药物敏感性的关键因素。我们的数据为治疗难治性耳念珠菌感染提供了新的治疗选择。耳念珠菌是一种新兴的多重耐药人类真菌病原体，几种抗真菌药物都难以治疗。与其他念珠菌不同，耳念珠菌可以长时间附着在人体皮肤上，从而在医院环境中实现有效的皮肤对皮肤传播。然而，明显的多药耐药和粘附特性的分子机制尚不清楚。双组分信号转导和丝裂原活化蛋白（MAP）激酶信号是粘附、抗真菌耐药性和毒力的重要调节因子。在这里，我们报道了遗传去除编码应答调节因子和丝裂原相关蛋白激酶HOG1的SSK1可以恢复C. auris临床菌株对两性霉素B （AMB）和caspofungin （CAS）的敏感性。SSK1和HOG1的缺失会改变细胞膜脂质通透性、细胞壁甘露聚糖含量以及对细胞壁扰动剂的高抗性。有趣的是，我们的数据显示SSK1和HOG1在不同的auris临床分离株中具有不同的功能，这表明SSK1和HOG1具有显著的遗传可塑性，影响细胞壁功能、应激适应和多药耐药性。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金黄色葡萄球菌对抗真菌药物的敏感性。耳念珠菌是一种新兴的耐多药真菌病原体，对人类健康构成严重的全球性威胁。美国疾病控制与预防中心（CDC）已将金黄色葡萄球菌列为未来十年对公众健康的紧急威胁，因为它具有重大的临床和经济影响，缺乏有效的抗真菌药物，而且未来还会出现新的金黄色葡萄球菌感染。重要的是，全球抗菌素耐药性监测系统（GLASS）强调需要更强大和有效的全球监测计划，以便识别和监测念珠菌感染的抗真菌耐药性。尽管耳念珠菌感染具有临床意义，但我们对其病理生理学和毒力、对人类免疫监测的反应以及多种抗真菌耐药性的分子基础的全面了解仍处于起步阶段。在这里，我们展示了金黄色葡萄球菌临床分离株的显著表型可塑性。此外，我们证明了应激反应机制在调节多药耐药中的关键作用，并表明细胞壁结构和组成是决定抗真菌药物敏感性的关键因素。我们的数据为治疗难治性耳念珠菌感染提供了新的治疗选择。
Candida auris is an emerging multidrug-resistant (MDR) fungal pathogen that presents a serious global threat to human health. The Centers for Disease Control and Prevention (CDC) have classified C. auris as an urgent threat to public health for the next decade due to its major clinical and economic impact and the lack of effective antifungal drugs and because of future projections concerning new C. auris infections. Importantly, the Global Antimicrobial Resistance Surveillance System (GLASS) has highlighted the need for more robust and efficacious global surveillance schemes enabling the identification and monitoring of antifungal resistance in Candida infections. Despite the clinical relevance of C. auris infections, our overall understanding of its pathophysiology and virulence, its response to human immune surveillance, and the molecular basis of multiple antifungal resistance remains in its infancy. Here, we show a marked phenotypic plasticity of C. auris clinical isolates. Further, we demonstrate critical roles of stress response mechanisms in regulating multidrug resistance and show that cell wall architecture and composition are key elements that determine antifungal drug susceptibilities. Our data promise new therapeutic options to treat drug-refractory C. auris infections. 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. IMPORTANCE Candida auris is an emerging multidrug-resistant (MDR) fungal pathogen that presents a serious global threat to human health. The Centers for Disease Control and Prevention (CDC) have classified C. auris as an urgent threat to public health for the next decade due to its major clinical and economic impact and the lack of effective antifungal drugs and because of future projections concerning new C. auris infections. Importantly, the Global Antimicrobial Resistance Surveillance System (GLASS) has highlighted the need for more robust and efficacious global surveillance schemes enabling the identification and monitoring of antifungal resistance in Candida infections. Despite the clinical relevance of C. auris infections, our overall understanding of its pathophysiology and virulence, its response to human immune surveillance, and the molecular basis of multiple antifungal resistance remains in its infancy. Here, we show a marked phenotypic plasticity of C. auris clinical isolates. Further, we demonstrate critical roles of stress response mechanisms in regulating multidrug resistance and show that cell wall architecture and composition are key elements that determine antifungal drug susceptibilities. Our data promise new therapeutic options to treat drug-refractory C. auris infections.
影响因子：
3.2
作者：
Menon V;De Bernardis F;Calderone R;Chauhan N
通讯作者：
Chauhan N