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
- 来源:
- 关键词:AddressAmino AcidsAnabolismAntibiotic ResistanceAntibioticsBiochemical ReactionBiogenesisBiologicalCarbonChemicalsChemistryClinicalClostridium difficileComplexCytochrome P450Cytochrome aCytochromesDataEngineeringEnzymesEthersFamilyGenerationsGlycopeptide AntibioticsGlycopeptidesGoalsHemeIn VitroInfectionKnowledgeLibrariesLigationLightMethodologyMethodsModificationNatural ProductsNatureOxidesPeptide SynthesisPeptidesPeroxidasesPharmaceutical PreparationsPhasePhenolsPlant ResinsProductionPropertyReactionReportingResearchResistanceResortRoleRouteSchemeScientistSeriesSolidSolventsStructureSuperbugSurfaceTherapeutic AgentsTimeVancomycinVariantanalogbasecatalystcofactorcrosslinkexperimental studyfascinateglobal healthglycosylationimprovedinnovationmembermetalloenzymemethicillin resistant Staphylococcus aureusnovelpathogenpathogenic bacteriaresistance mechanismstemweapons
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
糖肽类抗生素(Glycopeptide antibiotics,GPAs)是目前世界上最重要的抗生素之一。的
该天然产物家族的创始成员万古霉素被用作治疗感染的最后药物,
耐甲氧西林金黄色葡萄球菌(MRSA)和艰难梭菌。沿着其他一些
抗生素,万古霉素提供了一个重要的武器,对“超级细菌”,致病菌,
对多种临床抗生素获得性耐药。但是,随着对这最后一道防线的抵制蔓延,
开发化学定制万古霉素和其他GPA的方法来创造新的
对抗已知耐药机制的衍生物。
合成衍生化已被证明是创造新抗生素的成功方法,但这一方法不适用于抗生素。
这种方法在GPA中受到严格限制,主要是由于它们的化学复杂性和尺寸。的关键
万古霉素的结构复杂性和生物活性是三个芳香交联,由两个芳基
醚连接和联芳基碳-碳键。过去20年的研究表明,
细胞色素P450酶(OxyB)安装第一个芳基醚键。剩下的两个交叉点的来源,
然而,仍然难以捉摸。我们最近发现,第二种P450酶OxyA引入了第二种P450酶。
万古霉素生物发生过程中的芳基醚交联。我们进一步概括了OxyC的酶活性,
表明它安装了最终的联芳基连接,这是在任何GPA中首次演示此反应。此外,委员会认为,
我们已经利用天然生物合成金属酶的反应性来实现化学酶促反应,
产生万古霉素糖苷配基衍生物的途径。这个阶段是为了充分利用这种化学酶
方法化学衍生万古霉素,希望产生有用的第二代衍生物。
在本申请中,我们提出不仅完成万古霉素的化学-酶促合成,
而且还包括已知保留生物活性的衍生物,即使是针对抗性病原体。我们进一步建议,
建立万古霉素类似物的文库,我们称之为“设计师万古霉素”,含有修饰,
是无法用现有的方法来实现的。我们将同时探索详细的化学机制
的OxyB,并创建一个创新的固相方法,以提高我们的化疗的效率和可扩展性,
酶促途径我们的研究将揭示万古霉素的生物合成,并使最
全面的努力,但创造GPA变体具有独特的结构和可能的新的生物活性,通过
优雅的化学-酶促途径
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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