Exploration of novel mechanisms of azole resistance in Candida auris.

IF 4.1 2区 医学 Q2 MICROBIOLOGY
Antimicrobial Agents and Chemotherapy Pub Date : 2024-12-05 Epub Date: 2024-10-31 DOI:10.1128/aac.01265-24
Jizhou Li, Danielle Brandalise, Alix T Coste, Dominique Sanglard, Frederic Lamoth
{"title":"Exploration of novel mechanisms of azole resistance in <i>Candida auris</i>.","authors":"Jizhou Li, Danielle Brandalise, Alix T Coste, Dominique Sanglard, Frederic Lamoth","doi":"10.1128/aac.01265-24","DOIUrl":null,"url":null,"abstract":"<p><p><i>Candida auris</i> is a pathogenic yeast of particular concern because of its ability to cause nosocomial outbreaks of invasive candidiasis (IC) and to develop resistance to all current antifungal drug classes. Most <i>C. auris</i> clinical isolates are resistant to fluconazole, an azole drug that is used for the treatment of IC. Azole resistance may arise from diverse mechanisms, such as mutations of the target gene (<i>ERG11</i>) or upregulation of efflux pumps via gain of function mutations of the transcription factors <i>TAC1</i> and/or <i>MRR1</i>. To explore novel mechanisms of azole resistance in <i>C. auris</i>, we applied an <i>in vitro</i> evolutionary protocol to induce azole resistance in a <i>TAC1A</i>/<i>TAC1B</i>/<i>MRR1</i> triple-deletion strain. Azole-resistant isolates without <i>ERG11</i> mutations were further analyzed. In addition to a whole chromosome aneuploidy of chromosome 5, amino acid substitutions were recovered in the transcription factor Upc2 (N592S, L499F), the ubiquitin ligase complex consisting of Ubr2 (P708T, H1275P) and Mub1 (Y765*), and the mitochondrial protein Mrs7 (D293H). Genetic introduction of these mutations in an azole-susceptible wild-type <i>C. auris</i> isolate of clade IV resulted in significantly decreased azole susceptibility. Real-time reverse transcription PCR analyses were performed to assess the impact of these mutations on the expression of genes involved in azole resistance, such as <i>ERG11</i>, the efflux pumps <i>CDR1</i> and <i>MDR1</i> or the transcription factor <i>RPN4</i>. In conclusion, this work provides further insights in the complex and multiple pathways of azole resistance of <i>C. auris</i>. Further analyses would be warranted to assess their respective role in azole resistance of clinical isolates.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0126524"},"PeriodicalIF":4.1000,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619343/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Antimicrobial Agents and Chemotherapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1128/aac.01265-24","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/31 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Candida auris is a pathogenic yeast of particular concern because of its ability to cause nosocomial outbreaks of invasive candidiasis (IC) and to develop resistance to all current antifungal drug classes. Most C. auris clinical isolates are resistant to fluconazole, an azole drug that is used for the treatment of IC. Azole resistance may arise from diverse mechanisms, such as mutations of the target gene (ERG11) or upregulation of efflux pumps via gain of function mutations of the transcription factors TAC1 and/or MRR1. To explore novel mechanisms of azole resistance in C. auris, we applied an in vitro evolutionary protocol to induce azole resistance in a TAC1A/TAC1B/MRR1 triple-deletion strain. Azole-resistant isolates without ERG11 mutations were further analyzed. In addition to a whole chromosome aneuploidy of chromosome 5, amino acid substitutions were recovered in the transcription factor Upc2 (N592S, L499F), the ubiquitin ligase complex consisting of Ubr2 (P708T, H1275P) and Mub1 (Y765*), and the mitochondrial protein Mrs7 (D293H). Genetic introduction of these mutations in an azole-susceptible wild-type C. auris isolate of clade IV resulted in significantly decreased azole susceptibility. Real-time reverse transcription PCR analyses were performed to assess the impact of these mutations on the expression of genes involved in azole resistance, such as ERG11, the efflux pumps CDR1 and MDR1 or the transcription factor RPN4. In conclusion, this work provides further insights in the complex and multiple pathways of azole resistance of C. auris. Further analyses would be warranted to assess their respective role in azole resistance of clinical isolates.

探索白色念珠菌对唑类抗性的新机制。
念珠菌是一种特别令人担忧的致病酵母菌,因为它能够引起侵袭性念珠菌病(IC)的院内爆发,并对目前所有的抗真菌药物产生耐药性。大多数 C. auris 临床分离株对用于治疗 IC 的唑类药物氟康唑具有耐药性。唑类药物的耐药性可能来自多种机制,如靶基因(ERG11)突变或通过转录因子 TAC1 和/或 MRR1 的功能增益突变上调外排泵。为了探索唑耐药性的新机制,我们采用体外进化方案诱导 TAC1A/TAC1B/MRR1 三重缺失菌株产生唑耐药性。我们进一步分析了未发生ERG11突变的抗唑分离株。除了 5 号染色体的全染色体非整倍体外,转录因子 Upc2(N592S、L499F)、由 Ubr2(P708T、H1275P)和 Mub1(Y765*)组成的泛素连接酶复合物以及线粒体蛋白 Mrs7(D293H)也发生了氨基酸置换。将这些突变基因导入对唑类敏感的野生型 C. auris IV 支系分离物中,可显著降低对唑类的敏感性。实时反转录 PCR 分析评估了这些突变对参与唑抗性的基因表达的影响,如 ERG11、外排泵 CDR1 和 MDR1 或转录因子 RPN4。总之,这项研究进一步揭示了蛔虫对唑类抗性的复杂和多重途径。有必要进行进一步分析,以评估它们在临床分离株的唑类耐药性中各自的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
10.00
自引率
8.20%
发文量
762
审稿时长
3 months
期刊介绍: Antimicrobial Agents and Chemotherapy (AAC) features interdisciplinary studies that build our understanding of the underlying mechanisms and therapeutic applications of antimicrobial and antiparasitic agents and chemotherapy.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信