Experimental Evolution Identifies Adaptive Aneuploidy as a Mechanism of Fluconazole Resistance in Candida auris
Experimental Evolution Identifies Adaptive Aneuploidy as a Mechanism of Fluconazole Resistance in Candida auris
复制标题
DOI：
10.1128/aac.01466-20
复制
发表时间：
2021-01-01
影响因子：
4.9
通讯作者：
Huang, Guanghua
中科院分区：
文献类型：
--
作者：
Bing, Jian;Hu, Tianren;Huang, Guanghua
耳念珠菌是一种新发现的人类致病真菌，引起了临床和基础研究界的广泛关注。临床分离的C.耳通常对一种或多种抗真菌剂有抗性。为了探索抗真菌药的耐药性是如何发展的，我们使用氟康唑敏感的C. auris（BJCA001）。经过一系列的传代，通过培养基中含有浓度增加的氟康唑，真菌细胞获得抗性。通过对氟康唑敏感株和26株实验进化株的基因组进行测序和比较。在不加氟康唑的情况下，我们发现部分氟康唑耐药菌株携带一个额外的V染色体拷贝。基因组和转录组测序（RNA-Seq）分析表明，该染色体携带许多耐药相关基因，这些基因在耐药非整倍体菌株中转录上调。此外，在所有实验进化的菌株中，在基因TAC 1B、RRP 6和SFT 2中鉴定出错义突变。我们的研究结果表明，获得额外拷贝的染色体V与氟康唑耐药的快速获得有关，并可能代表了一个重要的抗真菌药物耐药的进化机制。耳。
Candida auris is a newly emerging fungal pathogen of humans and has attracted considerable attention from both the clinical and basic research communities. Clinical isolates of C. auris are often resistant to one or more antifungal agents. To explore how antifungal resistance develops, we performed experimental evolution assays using a fluconazole-susceptible isolate of C. auris (BJCA001). After a series of passages through medium containing increasing concentrations of fluconazole, fungal cells acquired resistance. By sequencing and comparing the genomes of the parental fluconazole-susceptible strain and 26 experimentally evolved strains of C. auris, we found that a portion of fluconazole-resistant strains carried one extra copy of chromosome V. In the absence of fluconazole, C. auris cells rapidly became susceptible and lost the extra copy of chromosome V. Genomic and transcriptome sequencing (RNA-Seq) analyses indicate that this chromosome carries a number of drug resistance-related genes, which were transcriptionally upregulated in the resistant, aneuploid strains. Moreover, missense mutations were identified in the genes TAC1B, RRP6, and SFT2 in all experimentally evolved strains. Our findings suggest that the gain of an extra copy of chromosome V is associated with the rapid acquisition of fluconazole resistance and may represent an important evolutionary mechanism of antifungal resistance in C. auris.