A Zinc Cluster Transcription Factor Contributes to the Intrinsic Fluconazole Resistance of Candida auris
A Zinc Cluster Transcription Factor Contributes to the Intrinsic Fluconazole Resistance of Candida auris
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DOI：
10.1128/msphere.00279-20
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发表时间：
2020-03-01
期刊：
影响因子：
4.8
通讯作者：
Morschhaeuser, Joachim
中科院分区：
文献类型：
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作者：
Mayr, Eva-Maria;Ramirez-Zavala, Bernardo;Morschhaeuser, Joachim
最近出现的致病性酵母菌念珠菌是人类健康的主要问题，因为它容易传播，难以从医院根除，并且具有高度耐药性。大部分C。由于靶酶Erg 11的突变和外排泵如Cdr 1的高活性，耳道分离株对广泛使用的抗真菌药物氟康唑具有抗性。在经过充分研究的远亲酵母菌白色念珠菌中，药物外排泵的过表达也是获得性氟康唑耐药的主要机制，并且是由锌簇转录因子Mrr 1和Tac 1的功能获得性突变引起的。本研究旨在探讨相关转录因子在外排泵表达和氟康唑耐药中的作用。耳。梭auris基因组包含3个编码Mrr 1同源物的基因和2个编码Tac 1同源物的基因，我们在来自进化枝III和进化枝IV的两个氟康唑抗性菌株中产生缺失这些基因的缺失突变体。TAC 1b的缺失降低了两种背景菌株对氟康唑和伏立康唑的耐药性，表明编码的转录因子有助于C.来自不同进化枝的auris菌株。CDR 1的表达没有或只有最低限度的影响，在突变体中，表明Tac 1b可以赋予增加唑类耐药的CDR 1-独立mechanism.IMPORTANCE耳念珠菌是最近出现的致病性酵母菌，在几年内，其最初的描述已经遍布地球仪。C.耳炎是人类健康的一个主要问题，因为它可引起危及生命的全身感染，易于传播，并且难以从医院环境中根除。此外，C.耳具有高度的耐药性，特别是对广泛使用的抗真菌药物氟康唑。药物靶点的突变和外排泵的高活性与唑类耐药有关，但目前尚不清楚耐药基因在C.耳。我们研究了几个候选转录调节因子在念珠菌内在氟康唑耐药中的潜在作用。并鉴定了一个转录因子，该转录因子与两株念珠菌对氟康唑和伏立康唑的高耐药性有关。auris菌株来自不同的遗传分支，从而提供深入了解这种医学上重要的酵母耐药性的分子基础。
The recently emerged pathogenic yeast Candida auris is a major concern for human health, because it is easily transmissible, difficult to eradicate from hospitals, and highly drug resistant. Most C. auris isolates are resistant to the widely used antifungal drug fluconazole due to mutations in the target enzyme Erg11 and high activity of efflux pumps, such as Cdr1. In the well-studied, distantly related yeast Candida albicans, overexpression of drug efflux pumps also is a major mechanism of acquired fluconazole resistance and caused by gain-of-function mutations in the zinc cluster transcription factors Mrr1 and Tac1. In this study, we investigated a possible involvement of related transcription factors in efflux pump expression and fluconazole resistance of C. auris. The C. auris genome contains three genes encoding Mrr1 homologs and two genes encoding Tac1 homologs, and we generated deletion mutants lacking these genes in two fluconazole-resistant strains from clade III and clade IV. Deletion of TAC1b decreased the resistance to fluconazole and voriconazole in both strain backgrounds, demonstrating that the encoded transcription factor contributes to azole resistance in C. auris strains from different clades. CDR1 expression was not or only minimally affected in the mutants, indicating that Tac1b can confer increased azole resistance by a CDR1-independent mechanism.IMPORTANCE Candida auris is a recently emerged pathogenic yeast that within a few years after its initial description has spread all over the globe. C. auris is a major concern for human health, because it can cause life-threatening systemic infections, is easily transmissible, and is difficult to eradicate from hospital environments. Furthermore, C. auris is highly drug resistant, especially against the widely used antifungal drug fluconazole. Mutations in the drug target and high activity of efflux pumps are associated with azole resistance, but it is not known how drug resistance genes are regulated in C. auris. We have investigated the potential role of several candidate transcriptional regulators in the intrinsic fluconazole resistance of C. auris and identified a transcription factor that contributes to the high resistance to fluconazole and voriconazole of two C. auris strains from different genetic clades, thereby providing insight into the molecular basis of drug resistance of this medically important yeast.