Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jerseygrid.430387.b, Newark, New Jersey, USA.
Department of Medical Biochemistry, Max Perutz Labs Vienna, Campus Vienna Biocenter, Medical University of Viennagrid.22937.3d, Vienna, Austria.
Antimicrob Agents Chemother. 2022 Jun 21;66(6):e0227621. doi: 10.1128/aac.02276-21. Epub 2022 Jun 2.
Candida auris is an emerging multidrug-resistant human fungal pathogen often refractory to treatment by all classes of antifungal drugs. Amphotericin B (AmB) is a fungicidal drug that, despite its toxic side effects, remains a drug of choice for the treatment of drug-resistant fungal infections, including those caused by C. auris. However, the molecular mechanisms underlying AmB resistance are poorly understood. In this study, we present data that suggests membrane lipid alterations and chromatin modifications are critical processes that may contribute to or cause adaptive AmB resistance in clinical C. auris isolates. To determine the plausible cause of increased AmB resistance, we performed RNA-seq of AmB-resistant and sensitive C. auris isolates. Remarkably, AmB-resistant strains show a pronounced enrichment of genes involved in lipid and ergosterol biosynthesis, adhesion, drug transport as well as chromatin remodeling. The transcriptomics data confirm increased adhesion and reduced lipid membrane permeability of AmB-resistant strains compared to the sensitive isolates. The AmB-resistant strains also display hyper-resistance to cell wall perturbing agents, including Congo red, calcofluor white and caffeine. Additionally, we noticed an increased phosphorylation of Mkc1 cell integrity MAP kinase upon AmB treatment. Collectively, these data identify differences in the transcriptional landscapes of AmB-resistant versus AmB-sensitive isolates and provide a framework for the mechanistic understanding of AmB resistance in C. auris.
耳念珠菌是一种新兴的、对多种抗真菌药物具有耐药性的人源真菌病原体，通常对所有类别的抗真菌药物治疗都有抗性。两性霉素 B（AmB）是一种杀真菌药物，尽管其具有毒性副作用，但仍然是治疗耐药性真菌感染的首选药物，包括由耳念珠菌引起的感染。然而，AmB 耐药的分子机制尚未得到充分理解。在这项研究中，我们提供的数据表明，膜脂质改变和染色质修饰是关键过程，可能有助于或导致临床耳念珠菌分离株的适应性 AmB 耐药。为了确定 AmB 耐药性增加的可能原因，我们对 AmB 耐药和敏感的耳念珠菌分离株进行了 RNA-seq 分析。值得注意的是，AmB 耐药株表现出明显富集与脂质和麦角固醇生物合成、粘附、药物转运以及染色质重塑相关的基因。转录组学数据证实，与敏感分离株相比，AmB 耐药株的粘附增加，脂质膜通透性降低。AmB 耐药株对细胞壁扰动剂（包括刚果红、钙荧光白和咖啡因）也表现出超耐药性。此外，我们注意到 AmB 处理后 Mkc1 细胞完整性 MAP 激酶的磷酸化增加。总之，这些数据确定了 AmB 耐药株与 AmB 敏感株之间转录谱的差异，并为理解耳念珠菌中 AmB 耐药的机制提供了框架。
