Genome-Wide Analysis of Experimentally Evolved Candida auris Reveals Multiple Novel Mechanisms of Multidrug Resistance.
Genome-Wide Analysis of Experimentally Evolved Candida auris Reveals Multiple Novel Mechanisms of Multidrug Resistance.
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DOI：
10.1128/mbio.03333-20
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发表时间：
2021-04-05
期刊：
影响因子：
6.4
通讯作者：
Van Dijck P
中科院分区：
文献类型：
--
作者：
Carolus H;Pierson S;Muñoz JF;Subotić A;Cruz RB;Cuomo CA;Van Dijck P
耳念珠菌是最近发现的人类真菌病原体，并已显示出对临床上最常用的所有类别的抗真菌药物产生多重和泛耐药性的惊人潜力。目前，C.由于这种进化潜力，耳内感染已被全球公认为高度关注的医院病原体。由于其广泛的多药耐药（MDR），耳念珠菌是全球公认的高度关注的机会致病真菌。然而，MDR的分子机制在很大程度上尚未探索。这是第一次对C.通过在体外连续暴露于唑类、多烯类和棘白菌素类而获得的耳。我们显示了在抗真菌药物耐药性的已知和未知基因中拷贝数变异和新突变的逐步积累。棘白菌素抗性伴随着FKS 1热点1中的密码子缺失和FKS 1“新”热点3中的取代。ERG 3和CIS 2的突变进一步增加棘白菌素MIC。唑类药物敏感性降低与转录因子TAC1b的突变和药物外排泵Cdr1的过表达、包含ERG 11的1号染色体的节段性重复和包含TAC1b的整个5号染色体的重复有关。后者与ERG 11、TAC1b和CDR 2的表达增加相关，但与CDR 1无关。ERG 3和ERG 11无义突变的同时出现显示出降低了阿替霉素B的敏感性，伴随着氟康唑的交叉耐药。MEC3（一种主要以其在DNA损伤稳态中的作用而闻名的基因）中的突变进一步增加了多烯MIC。总的来说，这项研究显示了C.耳，即使在一个分支，直到现在不与MDR（分支II），强调其临床重要性和未来研究的迫切性。
Candida auris is a recently discovered human fungal pathogen and has shown an alarming potential for developing multi- and pan-resistance toward all classes of antifungals most commonly used in the clinic. Currently, C. auris has been globally recognized as a nosocomial pathogen of high concern due to this evolutionary potential. Candida auris is globally recognized as an opportunistic fungal pathogen of high concern, due to its extensive multidrug resistance (MDR). Still, molecular mechanisms of MDR are largely unexplored. This is the first account of genome-wide evolution of MDR in C. auris obtained through serial in vitro exposure to azoles, polyenes, and echinocandins. We show the stepwise accumulation of copy number variations and novel mutations in genes both known and unknown in antifungal drug resistance. Echinocandin resistance was accompanied by a codon deletion in FKS1 hot spot 1 and a substitution in FKS1 “novel” hot spot 3. Mutations in ERG3 and CIS2 further increased the echinocandin MIC. Decreased azole susceptibility was linked to a mutation in transcription factor TAC1b and overexpression of the drug efflux pump Cdr1, a segmental duplication of chromosome 1 containing ERG11, and a whole chromosome 5 duplication, which contains TAC1b. The latter was associated with increased expression of ERG11, TAC1b, and CDR2 but not CDR1. The simultaneous emergence of nonsense mutations in ERG3 and ERG11 was shown to decrease amphotericin B susceptibility, accompanied with fluconazole cross-resistance. A mutation in MEC3, a gene mainly known for its role in DNA damage homeostasis, further increased the polyene MIC. Overall, this study shows the alarming potential for and diversity of MDR development in C. auris, even in a clade until now not associated with MDR (clade II), stressing its clinical importance and the urge for future research.