Multi-Omics And Synbio Enabled Discovery Of Antifungal Fernene Triterpenes
多组学和 Synbio 发现抗真菌蕨烯三萜
基本信息
- 批准号:10601431
- 负责人:
- 金额:$ 30万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-15 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAffectAnabolismAntifungal AgentsAspergillus fumigatusAspergillus nidulansBioinformaticsBiological AssayBiologyCandidaCandida albicansCandida aurisChemicalsChemistryClinicalCloningCyclizationDataDevelopmentDistantEngineeringEnzymesFamilyGene ClusterGenerationsGenesGenomeGenomicsGenotypeGlucoseGoalsHealthcare SystemsInfectionLeadLengthLifeLinkMarketingMass Spectrum AnalysisMeasuresMetabolicMethodsMiningMulti-Drug ResistanceMycosesNatural ProductsOralOrganismOutcomePathway interactionsPatientsPhenotypeProteinsRecording of previous eventsReportingResearchResourcesRestShuttle VectorsSignal TransductionStructureStructure-Activity RelationshipTechnologyTerpenesTherapeuticTimeTransferaseTriterpenesUniversitiesVariantVertebral columnWisconsinWorkanalogdesignfungusgenome analysisglucan synthaseglycosyltransferasehuman pathogeninhibitorinsightinterestmetabolic profilemetabolomicsmultiple omicsnovelnovel therapeuticspathogenic fungusprogramspromoterscaffoldsecondary metabolitesequencing platformsynthetic biologytoolwhole genome
项目摘要
Project Summary. A new functional metabologenomics approach is proposed for the development of a second
generation of fernene-based antifungal terpenes. Our team led by Mead (Varigen), Keller (University of
Wisconsin) and Kelleher (Northwestern University) explore the diversity of this unique family of triterpenes using
a fusion of technologies that unites genomics with metabolomic understanding of fungal terpene synthesis. We
begin by applying a genome mining-driven approach to find new natural analogs of enfumafungin. The resulting
data are then integrated with metabolomic analysis and antifungal bioactivity assay data to establish the putative
enfumafungin-like metabolites encoded by diverse strains and ultimately chart the structure-activity relationship
space within this potent class of antifungals. In parallel, our team is constructing a modular platform capable of
generating hundreds of different analogs in functional amounts. Here, we will heterologously express the
enfumafungin-like pathways from fungal strains in an engineered Aspergillus nidulans host. The sequence-
specific cloning and heterologous expression of lead molecules discovered in this program will establish methods
to conduct targeted swapping of cyclase genes across multiple species to generate new antifungal fernene-like
scaffolds. The long-term goal, requiring additional resources, is to advance a second generation of triterpene
antifungal analogs into the research and clinical market place. Overall, this program provides an important next
step towards establishing functional metabologenomics as a viable tool to go from genome to functional
therapeutic. As a testbed, we turn to a natural product family with a recent history of clinical utility for the
development of new analogs and technologies to access them.
项目摘要。提出了一种新的功能代谢基因组学方法,
基于蕨烯的抗真菌萜烯的产生。我们的团队由米德(瓦里根),凯勒(大学)
威斯康星州)和凯莱赫(西北大学)探索这种独特的三萜家族的多样性,
将基因组学与真菌萜烯合成的代谢组学理解结合起来的技术融合。我们
开始通过应用基因组挖掘驱动的方法来寻找恩夫马芬净的新的天然类似物。所得
然后将数据与代谢组学分析和抗真菌生物活性测定数据整合,以建立推定的
不同菌株编码的恩福霉素样代谢物,并最终绘制结构-活性关系
在这类强效抗真菌药物中占很大比例。与此同时,我们的团队正在构建一个模块化平台,
产生数百种不同的功能量的类似物。在这里,我们将异序表达
来自工程化构巢曲霉宿主中的真菌菌株的恩富霉素样途径。顺序是-
本计划中发现的先导分子的特异性克隆和异源表达将建立方法
在多个物种中进行环化酶基因的靶向交换,
脚手架长期的目标,需要额外的资源,是推进第二代三萜
抗真菌类似物进入研究和临床市场。总体而言,该计划提供了一个重要的下一个
建立功能代谢基因组学作为从基因组到功能
有治疗作用的作为一个试验平台,我们转向一个天然产品家族,该家族具有最近的临床应用历史,
开发新的类似物和技术来获取它们。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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NEIL L KELLEHER其他文献
NEIL L KELLEHER的其他文献
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{{ truncateString('NEIL L KELLEHER', 18)}}的其他基金
Chemistry of Life Processes Predoctoral Training Program
生命过程化学博士前培训项目
- 批准号:
10628231 - 财政年份:2023
- 资助金额:
$ 30万 - 项目类别:
Defining native proteoform landscape for amyloid-beta in Alzheimers disease
定义阿尔茨海默病中β淀粉样蛋白的天然蛋白质形态
- 批准号:
9803611 - 财政年份:2019
- 资助金额:
$ 30万 - 项目类别:
Renewable and Specific Affinity Reagents for Mapping Proteoforms in Human Tissues
用于绘制人体组织中蛋白质组图谱的可再生特异性亲和试剂
- 批准号:
9894469 - 财政年份:2019
- 资助金额:
$ 30万 - 项目类别:
Renewable and Specific Affinity Reagents for Mapping Proteoforms in Human Tissues
用于绘制人体组织中蛋白质组图谱的可再生特异性亲和试剂
- 批准号:
10249071 - 财政年份:2019
- 资助金额:
$ 30万 - 项目类别:
National Resource for Translational and Developmental Proteomics
国家转化和发育蛋白质组学资源
- 批准号:
9456539 - 财政年份:2017
- 资助金额:
$ 30万 - 项目类别:
Mapping and Understanding Production of Natural Products in Fungi
绘制和了解真菌天然产物的生产
- 批准号:
10677824 - 财政年份:2016
- 资助金额:
$ 30万 - 项目类别:
Mass Spectrometric Studies of Thiotemplate Biosynthesis
硫模板生物合成的质谱研究
- 批准号:
9240599 - 财政年份:2016
- 资助金额:
$ 30万 - 项目类别:
Mapping and Understanding Production of Natural Products in Fungi
绘制和了解真菌天然产物的生产
- 批准号:
10522724 - 财政年份:2016
- 资助金额:
$ 30万 - 项目类别:
Mass Spectrometric Studies of Thiotemplate Biosynthesis
硫模板生物合成的质谱研究
- 批准号:
9905491 - 财政年份:2016
- 资助金额:
$ 30万 - 项目类别:
National Resource for Translational and Developmental Proteomics
国家转化和发育蛋白质组学资源
- 批准号:
9283567 - 财政年份:2015
- 资助金额:
$ 30万 - 项目类别:
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