Non-cyp51A-mutation Mediated Triazole Resistance in Aspergillus fumigatus

非 cyp51A 突变介导的烟曲霉三唑耐药性

基本信息

项目摘要

A critical barrier to overcoming triazole resistance in Aspergillus fumigatus is the significant lack of understanding of its genetic and molecular basis. We have shown that the known mechanisms of resistance do not fully explain resistance observed among most clinical isolates. Our long-term goal is to improve antifungal therapy and ensure the sustained clinical utility of the triazole class for treatment of infections caused by Aspergillus species. Our central hypothesis is that non-cyp51A-mutation mediated mechanisms are essential to triazole resistance in clinical isolates of A. fumigatus and involve complex genetic changes altering 1) sterol biosynthesis and its transcriptional activation, 2) triazole transport and its transcriptional activation, and 3) as yet unknown mechanisms. Our current objective is to address critical knowledge gaps by identifying the genetic and molecular determinants of non-cyp51A-mutation mediated resistance. Our preliminary data suggest that while mutations in cyp51A among triazole resistant clinical isolates are common, their overall contribution to resistance is minimal. We have observed mutations, unique to resistant isolates in our collection, in genes encoding sterol sensing proteins, regulators of sterol biosynthesis, and sterol biosynthesis enzymes. We have also observed clinical isolates that overexpress not only cyp51A, but most genes of the ergosterol biosynthesis pathway, suggesting its constitutive activation. We have observed several potential transporters that are up- regulated among triazole resistant isolates in our collection, suggesting a role for triazole efflux and resistance by these transporters. We have also shown that clinical isolates of A. fumigatus take up triazole antifungals via facilitated diffusion and we believe that altered triazole import may represent an important mechanism of resistance. To accomplish our objective we will undertake experiments that will lead to an understanding of what genetic and molecular determinants influence triazole susceptibility through altered sterol biosynthesis or its transcriptional activation (Aim 1) and triazole transport and its regulation (Aim 2). In Aim 3, we will also utilize an unbiased whole genome comparisons, coupled with in vitro evolution experiments, to identify completely novel mechanisms of resistance in clinical isolates. Our approach is innovative as we will use the latest genetic and genomic techniques to study and discover novel non-cyp51A-mutation mediated mechanisms of triazole resistance that are operative in a U.S.-based collection of triazole resistant clinical isolates. The proposed research is significant as it represents a comprehensive analysis of the molecular and genetic basis of non- cyp51A-mutation mediated triazole resistance in A. fumigatus and will provide novel insights into ways in which triazole activity can be improved against this important human pathogen.
克服烟曲霉对三唑耐药性的一个关键障碍是缺乏

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Jarrod R. Fortwendel其他文献

MOB-mediated regulation of septation initiation network (SIN) signaling is required for echinocandin-induced hyperseptation in emAspergillus fumigatus/em
棘白菌素诱导烟曲霉超分隔需要 MOB 介导的分隔起始网络(SIN)信号调节
  • DOI:
    10.1128/msphere.00695-23
  • 发表时间:
    2024-02-20
  • 期刊:
  • 影响因子:
    3.100
  • 作者:
    Harrison I. Thorn;Xabier Guruceaga;Adela Martin-Vicente;Ashley V. Nywening;Jinhong Xie;Wenbo Ge;Jarrod R. Fortwendel;Rebecca S. Shapiro
  • 通讯作者:
    Rebecca S. Shapiro
emhapE/em and emhmg1/em Mutations Are Drivers of emcyp51A/em-Independent Pan-Triazole Resistance in an Aspergillus fumigatus Clinical Isolate
emhapE/em 和 emhmg1/em 突变是烟曲霉临床分离株中不依赖于 emcyp51A/em 的泛三唑抗性的驱动因素
  • DOI:
    10.1128/spectrum.05188-22
  • 发表时间:
    2023-05-18
  • 期刊:
  • 影响因子:
    3.800
  • 作者:
    Ana C. O. Souza;Wenbo Ge;Nathan P. Wiederhold;Jeffrey M. Rybak;Jarrod R. Fortwendel;P. David Rogers
  • 通讯作者:
    P. David Rogers

Jarrod R. Fortwendel的其他文献

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{{ truncateString('Jarrod R. Fortwendel', 18)}}的其他基金

Genetic Determinants of Aspergillus host-pathogen interactions
曲霉菌宿主-病原体相互作用的遗传决定因素
  • 批准号:
    10724816
  • 财政年份:
    2023
  • 资助金额:
    $ 65.73万
  • 项目类别:
Unlocking the cidal activity of echinocandins against Aspergillus fumigatus
解锁棘白菌素对烟曲霉的杀灭活性
  • 批准号:
    10378147
  • 财政年份:
    2021
  • 资助金额:
    $ 65.73万
  • 项目类别:
Unlocking the cidal activity of echinocandins against Aspergillus fumigatus
解锁棘白菌素对烟曲霉的杀灭活性
  • 批准号:
    10179720
  • 财政年份:
    2021
  • 资助金额:
    $ 65.73万
  • 项目类别:
Unlocking the cidal activity of echinocandins against Aspergillus fumigatus
解锁棘白菌素对烟曲霉的杀灭活性
  • 批准号:
    10590730
  • 财政年份:
    2021
  • 资助金额:
    $ 65.73万
  • 项目类别:
Non-cyp51A-mutation Mediated Triazole Resistance in Aspergillus fumigatus
非 cyp51A 突变介导的烟曲霉三唑耐药性
  • 批准号:
    9913275
  • 财政年份:
    2020
  • 资助金额:
    $ 65.73万
  • 项目类别:
Non-cyp51A-mutation Mediated Triazole Resistance in Aspergillus fumigatus
非 cyp51A 突变介导的烟曲霉三唑耐药性
  • 批准号:
    10358515
  • 财政年份:
    2020
  • 资助金额:
    $ 65.73万
  • 项目类别:
Fungal Ras-mediated invasive growth mechanisms
真菌 Ras 介导的侵袭性生长机制
  • 批准号:
    9282239
  • 财政年份:
    2014
  • 资助金额:
    $ 65.73万
  • 项目类别:
Fungal Ras-mediated invasive growth mechanisms
真菌 Ras 介导的侵袭性生长机制
  • 批准号:
    8806512
  • 财政年份:
    2014
  • 资助金额:
    $ 65.73万
  • 项目类别:
Fungal Ras-mediated invasive growth mechanisms
真菌 Ras 介导的侵袭性生长机制
  • 批准号:
    9205482
  • 财政年份:
    2014
  • 资助金额:
    $ 65.73万
  • 项目类别:
Fungal Ras-mediated invasive growth mechanisms
真菌 Ras 介导的侵袭性生长机制
  • 批准号:
    8696215
  • 财政年份:
    2014
  • 资助金额:
    $ 65.73万
  • 项目类别:

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