Toward a Chemo-Enzymatic Synthesis of Vancomycin and Its Analogs

万古霉素及其类似物的化学酶法合成

基本信息

  • 批准号:
    10439760
  • 负责人:
  • 金额:
    $ 31.03万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-07-01 至 2023-06-30
  • 项目状态:
    已结题

项目摘要

ABSTRACT Glycopeptide antibiotics (GPAs) are among the most important therapeutic agents world-wide. The founding member of this natural product family, vancomycin, is used a drug of last resort against infections by methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile. Along with a handful of other antibiotics, vancomycin provides an important weapon against “superbugs”, pathogenic bacteria that have acquired resistance to multiple clinical antibiotics. But as resistance to even this last line of defense spreads, it is ever more important to develop means of chemically tailoring vancomycin and other GPAs to create new derivatives that counter known resistance mechanisms. Synthetic derivatization has proven to be a successful method for creating new antibiotics, but this approach is severely restricted within the GPAs, primarily due to their chemical complexity and size. Key to the structural complexity and biological activity of vancomycin are three aromatic crosslinks, consisting of two aryl ether connections and a biaryl carbon-carbon bond. Research over the past 20 years has shown that a cytochrome P450 enzyme (OxyB) installs the first aryl ether bond. The origin of the remaining two crosslinks, however, remained elusive. We recently showed that OxyA, a second P450 enzyme, introduces the second aryl ether crosslink during vancomycin biogenesis. We further recapitulated the enzymatic activity of OxyC and showed that it installs the final biaryl connection, the first demonstration of this reaction in any GPA. Moreover, we have exploited the reactivities of the native biosynthetic metalloenzymes to implement a chemo-enzymatic route for creating a vancomycin aglycone derivative. The stage is set to fully leverage this chemo-enzymatic approach to chemically derivatize vancomycin in the hopes of generating useful second-generation derivatives. In the current application, we propose to complete the chemo-enzymatic synthesis of not just vancomycin, but also of derivatives known to retain bioactivity, even against resistant pathogens. We further propose to build a library of vancomycin analogs that we refer to as “designer vancomycins”, containing modifications that are inaccessible with current methodologies. We will simultaneously explore the detailed chemical mechanism of OxyB and create an innovative solid-phase approach to enhance the efficiency and scalability of our chemo- enzymatic route. Our studies will shed light onto the biosynthesis of vancomycin and enable the most comprehensive effort yet to create GPA variants with unique structures and possibly new bioactivities via an elegant chemo-enzymatic route.
摘要

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Mapping and Exploiting the Promiscuity of OxyB toward the Biocatalytic Production of Vancomycin Aglycone Variants.
  • DOI:
    10.1021/acscatal.0c01719
  • 发表时间:
    2020-08-21
  • 期刊:
  • 影响因子:
    12.9
  • 作者:
    Forneris CC;Nguy AKL;Seyedsayamdost MR
  • 通讯作者:
    Seyedsayamdost MR
Robust Chemoenzymatic Synthesis of Keratinimicin Aglycone Analogues Facilitated by the Structure and Selectivity of OxyB.
  • DOI:
    10.1021/acschembio.3c00192
  • 发表时间:
    2023-07-21
  • 期刊:
  • 影响因子:
    4
  • 作者:
    Hauser N;Ireland KA;Chioti VT;Forneris CC;Davis KM;Seyedsayamdost MR
  • 通讯作者:
    Seyedsayamdost MR
Biosynthesis of selenium-containing small molecules in diverse microorganisms
  • DOI:
    10.1038/s41586-022-05174-2
  • 发表时间:
    2022-09-07
  • 期刊:
  • 影响因子:
    64.8
  • 作者:
    Kayrouz, Chase M.;Huang, Jonathan;Seyedsayamdost, Mohammad R.
  • 通讯作者:
    Seyedsayamdost, Mohammad R.
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Mohammad R Seyedsayamdost其他文献

Mohammad R Seyedsayamdost的其他文献

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{{ truncateString('Mohammad R Seyedsayamdost', 18)}}的其他基金

Exploring a New Dimension of Microbial Secondary Metabolism
探索微生物次生代谢的新维度
  • 批准号:
    10298182
  • 财政年份:
    2021
  • 资助金额:
    $ 31.03万
  • 项目类别:
Exploring a New Dimension of Microbial Secondary Metabolism
探索微生物次生代谢的新维度
  • 批准号:
    10623226
  • 财政年份:
    2021
  • 资助金额:
    $ 31.03万
  • 项目类别:
Exploring a New Dimension of Microbial Secondary Metabolism
探索微生物次生代谢的新维度
  • 批准号:
    10443867
  • 财政年份:
    2021
  • 资助金额:
    $ 31.03万
  • 项目类别:
Toward a Chemo-Enzymatic Synthesis of Vancomycin and Its Analogs
万古霉素及其类似物的化学酶法合成
  • 批准号:
    10170408
  • 财政年份:
    2019
  • 资助金额:
    $ 31.03万
  • 项目类别:
Implementing Innovative Approaches to Access the Hidden Metabolomes of Bacteria
实施创新方法来获取细菌隐藏的代谢组
  • 批准号:
    8955195
  • 财政年份:
    2015
  • 资助金额:
    $ 31.03万
  • 项目类别:
Molecular Analysis of Metabolites and Signaling Networks in Microbial Symbioses
微生物共生中代谢物和信号网络的分子分析
  • 批准号:
    8164434
  • 财政年份:
    2011
  • 资助金额:
    $ 31.03万
  • 项目类别:
Molecular Analysis of Metabolites and Signaling Networks in Microbial Symbioses
微生物共生中代谢物和信号网络的分子分析
  • 批准号:
    8627615
  • 财政年份:
    2011
  • 资助金额:
    $ 31.03万
  • 项目类别:
Molecular Analysis of Metabolites and Signaling Networks in Microbial Symbioses
微生物共生中代谢物和信号网络的分子分析
  • 批准号:
    8609131
  • 财政年份:
    2011
  • 资助金额:
    $ 31.03万
  • 项目类别:
Molecular Analysis of Metabolites and Signaling Networks in Microbial Symbioses
微生物共生中代谢物和信号网络的分子分析
  • 批准号:
    8306940
  • 财政年份:
    2011
  • 资助金额:
    $ 31.03万
  • 项目类别:

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