Regulation of Multidrug Resistance in the Emerging Human Fungal Pathogen Candida auris

新兴人类真菌病原体耳念珠菌的多药耐药性调控

基本信息

批准号：
10409832
负责人：
DAVID KADOSH
金额：
$ 23.25万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-24 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10409832
关键词：
5&apos Untranslated Regions Acquired Immunodeficiency Syndrome Address Amphotericin B Antifungal Agents Azole resistance Azoles Bioinformatics Cancer Patient Candida Candida albicans Candida auris Candidiasis Centers for Disease Control and Prevention (U.S.)Development Disease Outbreaks Drug Efflux Drug resistance Event Filament Fluconazole Fluconazole resistance Fungal Drug Resistance Gene Expression Gene Expression Profiling Genes Genetic Genetic Transcription Goals Hospitals Human Immunocompromised Host Individual Infection Laboratories Lanosterol Mediating Microbial Biofilms Monitor Morphology Mucous Membrane Multi-Drug Resistance Mutation Open Reading Frames Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Play Point Mutation Polyenes Predisposition Process Property Protein Biosynthesis Proteins Proxy Public Health Regulation Resistance Ribosomes Role Site Skin Surface Testing Translational Regulation Translations Treatment Protocols Virulence Work Yeasts base chemotherapy effective therapy efflux pump genome-wide mortality mutant new therapeutic target novel novel therapeutics organ transplant recipient overexpression pathogen pathogenic fungus protein expression resistance frequency resistance mechanism response ribosome profiling therapeutically effective trait transcriptome transcriptome sequencing treatment response virtual whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Candida auris is a rapidly emerging human fungal pathogen capable of causing both systemic and mucosal infections in a wide variety of immunocompromised individuals, including organ transplant recipients, cancer patients on chemotherapy and AIDS patients. C. auris has emerged on multiple continents, is responsible for numerous hospital outbreaks and, with a high crude mortality rate (30-70%), has been classified as an “urgent” threat to public health by the Centers for Disease Control (CDC). Many C. auris isolates are highly resistant to multiple classes of antifungals, particularly azoles and polyenes, which is especially concerning given that only three major drug classes are available to treat patients with candidiasis. Previous studies have shown that C. auris antifungal resistance can be attributed to a variety of genetic point mutations (eg: mutations in ERG11, encoding lanosterol 14α-demethylase, the target of azoles) as well as increased transcription of certain drug efflux pumps. In contrast to genetic and transcriptional mechanisms, very little is known about translational mechanisms that control antifungal resistance in C. auris or other human fungal pathogens. However, our laboratory and others, have shown that 5' UTR-mediated translational efficiency mechanisms play an important role in controlling the expression of several key transcriptional regulators of morphology, biofilm formation, white-opaque switching and virulence in the related major human fungal pathogen Candida albicans. In addition, RNA-seq analyses have shown that many genes involved in a variety of additional virulence processes, including antifungal resistance, in C. albicans and other Candida species possess long 5' UTR regions that could be involved in translational regulation. Using genome-wide ribosome profiling, we have recently demonstrated that the C. albicans yeast-filament transition is under widespread translational control that does not simply parallel transcriptional changes in gene expression. Several genes associated with antifungal resistance also showed altered translational efficiency during this transition. Importantly, recent transcriptional profiling of a multidrug resistant C. auris isolate has demonstrated that a significant number of genes involved in protein synthesis show altered expression in response to antifungal treatment. Based on these observations, we hypothesize that translational mechanisms play an important role in controlling multidrug resistance in C. auris. In order to address this hypothesis, we will: 1) determine the genome-wide translational profile of C. auris in response to treatment with fluconazole, a commonly used azole, and the polyene drug amphotericin B, 2) identify and characterize translational mechanisms important for promoting C. auris multidrug resistance. Ultimately, this study will provide a better understanding of global regulatory circuits and pathways that control C. auris multidrug resistance at the translational level. In addition, this study will identify and characterize several key translationally regulated factors important for C. auris multidrug resistance that could potentially serve as targets for the development of novel antifungal strategies.

项目摘要/摘要念珠菌是一种迅速出现的人类真菌病原体，能够同时引起全身和粘膜多种免疫功能低下的个体感染，包括器官移植受者，癌症化学疗法和艾滋病患者的患者。 C. Auris已在多大洲出现，负责许多医院暴发，高死亡率高（30-70％）被归类为“紧急” 疾病控制中心（CDC）对公共卫生的威胁。许多C. auris分离株对多种类别的抗真菌剂，尤其是偶氮和多烯，这尤其考虑到只有有三个主要的药物类别可用于治疗念珠菌病患者。先前的研究表明C. Auris抗真菌抗性可以归因于多种遗传点突变（例如：ERG11中的突变，编码羊毛醇14α-甲基酶，唑的靶标），并增加了某些药物的转录外排泵。与遗传和转录机制相反，关于翻译知之甚少控制抗真菌抗体的机制或其他人类真菌病原体中的抗真菌抗性。但是，我们的实验室和其他人已经表明，5'UTR介导的翻译效率机制起着重要的作用控制形态形成的几个关键转录调节剂的表达中的作用，生物膜形成，相关的主要人类真菌病原体白色念珠菌中的白色斑点转换和病毒。此外，RNA-Seq分析表明，许多涉及多种其他病毒的基因白色念珠菌和其他念珠菌中的过程，包括抗真菌抗性，具有长5'UTR 可能参与翻译调节的地区。使用全基因组核糖体分析，我们有最近证明，白色念珠菌酵母丝过渡处于宽度的转化控制下这不仅仅是基因表达中的转录变化。与在此转变过程中，抗真菌抗性也显示出改变的转化效率。重要的是，最近多药抗性C. auris分离株的转录分析已证明大量数量参与蛋白质合成的基因对抗真菌治疗的反应显示出改变的表达。基于这些观察结果，我们假设翻译机制在控制中起着重要作用 C. Auris中的多药抗性。为了解决这一假设，我们将：1）确定全基因组 Auris C. c. to氟康唑的治疗，一种常用争曲唑的翻译曲线，多烯药物两性霉素B，2）识别并表征了对促进C的转化机制。 Auris多药电阻。最终，这项研究将更好地了解全球监管电路以及控制C. auris多药电阻的途径。此外，这项研究将识别并表征几个关键翻译受调节的因素，对C. ouris MultiDrug重要有可能成为发展新型抗真菌策略的目标的抵抗力。