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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.

项目总结/文摘