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:
  • 金额:
    $ 23.25万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Perspective on the origin, resistance, and spread of the emerging human fungal pathogen Candida auris.
  • DOI:
    10.1371/journal.ppat.1011190
  • 发表时间:
    2023-03
  • 期刊:
  • 影响因子:
    6.7
  • 作者:
  • 通讯作者:
Post-transcriptional control of antifungal resistance in human fungal pathogens.
人类真菌病原体抗真菌耐药性的转录后控制。
  • DOI:
    10.1080/1040841x.2022.2080527
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    6.5
  • 作者:
    Sharma,Cheshta;Kadosh,David
  • 通讯作者:
    Kadosh,David
Rapid Proliferation Compensates for Defective Filamentation in Candida albicans Pathogenesis.
  • DOI:
    10.1016/j.tim.2021.08.006
  • 发表时间:
    2021-10
  • 期刊:
  • 影响因子:
    15.9
  • 作者:
    Kadosh D
  • 通讯作者:
    Kadosh D
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DAVID KADOSH其他文献

DAVID KADOSH的其他文献

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{{ truncateString('DAVID KADOSH', 18)}}的其他基金

Translational Regulation of Candida glabrata Azole Resistance
光滑念珠菌唑耐药性的转化调控
  • 批准号:
    10681915
  • 财政年份:
    2023
  • 资助金额:
    $ 23.25万
  • 项目类别:
Regulation of Candida albicans gene expression in response to host environmental stresses
白色念珠菌基因表达响应宿主环境胁迫的调节
  • 批准号:
    10867738
  • 财政年份:
    2023
  • 资助金额:
    $ 23.25万
  • 项目类别:
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
  • 批准号:
    10317488
  • 财政年份:
    2021
  • 资助金额:
    $ 23.25万
  • 项目类别:
Translational Control of Morphology and Virulence in Candida albicans
白色念珠菌形态和毒力的转化控制
  • 批准号:
    9910361
  • 财政年份:
    2018
  • 资助金额:
    $ 23.25万
  • 项目类别:
Translational Control of Morphology and Virulence in Candida albicans
白色念珠菌形态和毒力的转化控制
  • 批准号:
    10398003
  • 财政年份:
    2018
  • 资助金额:
    $ 23.25万
  • 项目类别:
Determination of morphology and virulence in Candida albicans
白色念珠菌形态和毒力的测定
  • 批准号:
    8260211
  • 财政年份:
    2010
  • 资助金额:
    $ 23.25万
  • 项目类别:
Determination of morphology and virulence in Candida albicans
白色念珠菌形态和毒力的测定
  • 批准号:
    8463967
  • 财政年份:
    2010
  • 资助金额:
    $ 23.25万
  • 项目类别:
Determination of morphology and virulence in Candida albicans
白色念珠菌形态和毒力的测定
  • 批准号:
    8071573
  • 财政年份:
    2010
  • 资助金额:
    $ 23.25万
  • 项目类别:
Determination of morphology and virulence in Candida albicans
白色念珠菌形态和毒力的测定
  • 批准号:
    8474527
  • 财政年份:
    2010
  • 资助金额:
    $ 23.25万
  • 项目类别:
Determination of morphology and virulence in Candida albicans
白色念珠菌形态和毒力的测定
  • 批准号:
    7898091
  • 财政年份:
    2010
  • 资助金额:
    $ 23.25万
  • 项目类别:

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