Genomics Accelerated Natural Product Discovery
基因组学加速天然产物发现
基本信息
- 批准号:10793456
- 负责人:
- 金额:$ 12.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAlgorithmsAnabolismAnimalsBacteriaBig DataBioinformaticsBiologicalBiologyChemicalsClassificationDataDevelopmentDrug KineticsEmerging TechnologiesEnzymesGene StructureGeneticGenomeGenomicsGeographyInvertebratesKnowledgeLengthLifeMacrolidesMetabolicMetagenomicsMiningModernizationMolecularMolecular ProbesMolecular StructureNatural ProductsNatural Products ChemistryNatural SourcePathway interactionsPharmaceutical PreparationsPolyenesProcessResourcesShapesSoilSourceStreptomycesStructureTaxonomyToxic effectgenomic datahuman diseaseimprovedinnovationinterestmetagenomemicrobialmicrobiomemicrobiome sequencingnovelscreeningsymbiontsynthetic biologytooluser-friendly
项目摘要
Our group is broadly interested in the chemical biology of natural products (NPs). We seek to identify new mo-
lecular structures that are formed by unusual enzymatic transformations. One successful approach was the de-
velopment of an innovative discovery workflow that embraces big data genomics. With the sequencing revolution
picking up pace, we are leveraging this vast resource to bioinformatically identify, classify, and experimentally
characterize carefully selected novel NPs. For this project, we focus on bacterial NPs for several reasons: (i)
Bacteria are the most historically significant source of molecular probes and drug leads. Such compounds re-
vealed fundamentally new biology and also transformed the treatment of many human diseases. (ii) Bacteria
dominate all other forms of life in terms of genetic/taxonomic breadth, chemical/metabolic capabilities, and geo-
graphic/environmental diversity. (iii) Bacteria tend to organize the genes involved in NP biosynthesis into neatly
organized clusters, which facilitates their bioinformatic identification and subsequent experimental characteriza-
tion. This proposal unites big data genomics, synthetic biology, and modern chemical biology to structurally and
functionally characterize novel NPs. Herein we target pathways predicted to showcase the molecular results of
new enzymatic transformations with a strong focus on metagenome-derived pathways, especially from bacteria
that associate with invertebrate animals.
Several readily cultivated bacterial genera have been extensively studied, which established certain taxa as
prolific sources of NPs (e.g. soil-dwelling Streptomyces). However, knowledge is sparse on less cultivable bac-
teria, which represent the overwhelming majority of microbial diversity. Only relatively recently have the requisite
technologies emerged to sequence and assemble metagenomic data into reads of useful length. As part of this
project, we have repurposed RODEO, our open access, user-friendly genome-mining tool to analyze data deriv-
ing from metagenome/microbiome sequencing projects. “MetaRODEO” will be validated through isolation and
characterization of several distinct NP classes. We center our efforts on NPs from symbiotic bacteria of inverte-
brates, given that numerous species have longstanding and intimate partnerships with their lower animal hosts.
Evolutionary forces have undoubtedly shaped the bioactivity, improved the pharmacokinetics, and reduced the
animal toxicity of NPs from bacterial symbionts compared to soil-dwelling counterparts.
This project involves three interconnected but independently achievable specific aims. Aim I focuses on genomic
sequencing, bioinformatics analysis, and isolation/characterization of first-in-class RiPPs from the invertebrate
microbiome. Aim II centers on new RiPPs and other NPs derived from microbiome-derived biosynthetic path-
ways that employ radical SAM enzymes. Aim III expands the environmental origin and chemistry of NPs identi-
fied by our algorithm by targeting polyene macrolides. Each aim will elucidate new NP structures and evaluate
biological activity using a rigorous, multi-tiered strategy.
我们的团队对天然产物(NPs)的化学生物学非常感兴趣。我们寻求识别新的mo-
项目成果
期刊论文数量(17)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Douglas Alan Mitchell其他文献
Douglas Alan Mitchell的其他文献
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{{ truncateString('Douglas Alan Mitchell', 18)}}的其他基金
A Scalable Platform to Discover Antimicrobials of Ribosomal Origin
发现核糖体来源抗菌药物的可扩展平台
- 批准号:
9899917 - 财政年份:2019
- 资助金额:
$ 12.09万 - 项目类别:
A Scalable Platform to Discover Antimicrobials of Ribosomal Origin
发现核糖体来源抗菌药物的可扩展平台
- 批准号:
10570218 - 财政年份:2019
- 资助金额:
$ 12.09万 - 项目类别:
A Scalable Platform to Discover Antimicrobials of Ribosomal Origin
发现核糖体来源抗菌药物的可扩展平台
- 批准号:
10359678 - 财政年份:2019
- 资助金额:
$ 12.09万 - 项目类别:
Genomics-Accelerated Natural Product Discovery
基因组学-加速天然产物发现
- 批准号:
10391633 - 财政年份:2017
- 资助金额:
$ 12.09万 - 项目类别:
Characterization of YcaO-Dependent Natural Product Biosynthetic Pathways
YcaO 依赖性天然产物生物合成途径的表征
- 批准号:
10389609 - 财政年份:2012
- 资助金额:
$ 12.09万 - 项目类别:
Characterization of YcaO-Dependent Natural Product Biosynthetic Pathways
YcaO 依赖性天然产物生物合成途径的表征
- 批准号:
10220046 - 财政年份:2012
- 资助金额:
$ 12.09万 - 项目类别:
Characterization of YcaO-Dependent Natural Product Biosynthetic Pathways
YcaO 依赖性天然产物生物合成途径的表征
- 批准号:
10457879 - 财政年份:2012
- 资助金额:
$ 12.09万 - 项目类别:
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