Balla Noémi, Kovács Fruzsina, Tóth Zoltán, Harmath Andrea, Bozó Aliz, Majoros László, Kovács Renátó, Jakab Ágnes
Department of Medical Microbiology, Faculty of Medicine, University of Debrecen, Nagyerdei Krt. 98., Debrecen, 4032, Hungary.
Doctoral School of Pharmaceutical Sciences, University of Debrecen, Debrecen, Hungary.
Mycopathologia. 2024 Dec 27;190(1):5. doi: 10.1007/s11046-024-00919-1.
The sudden emergence of multidrug- and pan-resistant Candida auris isolates, combined with limited treatment options, poses significant global challenges in healthcare settings. Combination based therapies are promising alternative options to overcome C. auris related infections, where echinocandin and isavuconazole (ISA) combinations may be an interesting and promising approach. Understanding the molecular mechanisms underlying ISA treatment is crucial for developing novel therapeutic recommendations. Therefore, we investigated the gene transcription profiles of non-wild type (non-WT) and wild type (WT) C. auris isolates from the South Asian clade following ISA exposure using total RNA sequencing. The non-WT isolate was classified according to the previously reported tentative epidemiological cut-off value of ≤ 1 mg/L. ISA treatment resulted in the upregulation of 158 and 134 genes and the downregulation of 119 and 96 genes in the non-WT and WT isolates, respectively, compared with untreated samples. In general, ISA-treated isolates exhibited increased transcription of the transcriptional factor UPC2, the drug transporter MDR1, vacuolar calcium-ATPase PMC1, and several ergosterol biosynthesis genes. The WT isolate showed pronounced enrichment of genes involved in sphingolipid biosynthesis, adhesion, and drug transport. These findings suggest that alterations in membrane lipid composition and modulation of drug efflux transporters are critical processes contributing to ISA susceptibility in case of WT isolates.
多重耐药和泛耐药耳念珠菌分离株的突然出现，加上治疗选择有限，给医疗机构带来了重大的全球挑战。基于联合用药的疗法是克服耳念珠菌相关感染的有前景的替代选择，其中棘白菌素和艾沙康唑（ISA）联合用药可能是一种有趣且有前景的方法。了解ISA治疗的分子机制对于制定新的治疗建议至关重要。因此，我们使用全RNA测序研究了来自南亚分支的非野生型（非WT）和野生型（WT）耳念珠菌分离株在接触ISA后的基因转录谱。非WT分离株根据先前报道的≤1 mg/L的暂定流行病学临界值进行分类。与未处理的样本相比，ISA处理导致非WT和WT分离株中分别有158个和134个基因上调，119个和96个基因下调。总体而言，经ISA处理的分离株表现出转录因子UPC2、药物转运蛋白MDR1、液泡钙ATP酶PMC1以及几个麦角固醇生物合成基因的转录增加。WT分离株显示参与鞘脂生物合成、黏附和药物转运的基因有明显富集。这些发现表明，膜脂成分的改变和药物外排转运蛋白的调节是导致WT分离株对ISA敏感的关键过程。
