Discovery of Antibiotics from Soil Microbiomes Using Metagenomics
利用宏基因组学从土壤微生物组中发现抗生素
基本信息
- 批准号:9906905
- 负责人:
- 金额:$ 67.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-05-01 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:AnabolismAntibioticsBacteriaBacterial Antibiotic ResistanceBase SequenceBiologicalBiological AssayCategoriesClinicalDNA SequenceDrug resistanceEnvironmentGene ClusterGenesGenomeHarvestHigh-Throughput Nucleotide SequencingIndividualInfectionLaboratoriesLaboratory cultureLeadLibrariesMetagenomicsMethodsNatural ProductsPhenotypePlanet EarthProtocols documentationRecording of previous eventsRewardsSamplingSeriesSoilSourceStructureSurfaceTimeUnited StatesWorkbaseclinical developmentclinically relevantcombatcost effectivedesignimprovedinterestmetagenomemicrobiomenovelpathogenic bacteriascreeningsmall molecule
项目摘要
Project summary: Drug-resistant infections kill more than 65,000 people in the United States per year and
the identification of new antibiotics capable of combating antibiotic resistant bacterial pathogens is desperately
needed. Bacterial natural products have a long proven history of being good lead structures for the
development of clinically useful antibiotics but, unfortunately, the discovery of novel natural products from
cultured bacteria has dramatically slowed in recent years. During the same time, the advent of cost effective
high-throughput sequencing and an increasingly sophisticated understanding of bacterial secondary metabolite
biosynthesis have led to two important revelations with respect to the search for new natural products: first,
that the biosynthetic potential of most cultured bacteria, as judged by the number of biosynthetic gene clusters
observed in sequenced genomes, is far greater than previously estimated; second, that the number of bacterial
species in most environments is at least one hundred times greater than the number of species that is readily
cultured. These observations indicate that conventional natural product screening approaches, which rely on
laboratory culturing of random bacterial strains from the environment, have not come close to realizing the full
biosynthetic potential of the earth's microbiome and that a fundamental change in the approach to bacterial
natural products discovery is therefore needed. Consequently, my laboratory has sought to develop methods
to allow natural product discovery from environmental samples, without the need for strain isolation and
cultivation. The approaches I propose to use to harvest small molecules from metagenomic libraries are
divided into two general categories: 1) Sequence-based metagenomics, which relies on DNA sequence
similarity to identify clones containing a specific gene of interest and 2) Function-based metagenomics, which
relies on the random, unbiased screening of individual eDNA clones in phenotypic assays to identify clones
producing bioactive metabolites. Using sequence-based approaches we can interrogate metagenomes for
novel gene clusters (i.e., new antibiotics), as well as clusters that encode congeners of clinically relevant
natural product (i.e., improve the utility of clinically important classes of antibiotics). Our functional screening
studies will focus on developing methods for creating metagenomic libraries that are enriched in natural
product gene clusters to facilitate more efficient screening for novel antibiotics. For this proposal, we will use
our existing pipelines and improved protocols, as they come on-line, to identify novel natural products with
improved activities against antibiotic resistant bacterial pathogens. We have undoubtedly just begun to scratch
the surface of what lies hidden in the genomes of environmental bacteria. The work here will greatly increase
access to the natural products that remain hidden in the environment and ultimately yield a series of novel
natural antibiotics with the potential to better treat antibiotic resistant bacterial pathogens.
!
耐药性感染每年在美国造成超过65,000人死亡,
能够对抗抗生素抗性细菌病原体的新抗生素的鉴定迫切需要
needed.细菌天然产物具有长期被证明是用于微生物的良好先导结构的历史。
开发临床有用的抗生素,但不幸的是,发现新的天然产物,
近年来,培养细菌的速度急剧下降。与此同时,成本效益的出现
高通量测序和对细菌次级代谢产物日益复杂的理解
生物合成导致了关于寻找新的天然产物的两个重要启示:首先,
大多数培养细菌的生物合成潜力,根据生物合成基因簇的数量来判断,
在测序的基因组中观察到的,远远大于先前的估计;第二,细菌的数量
在大多数环境中,物种的数量至少是容易找到的物种数量的一百倍。
有教养这些观察结果表明,传统的天然产品筛选方法依赖于
从环境中随机细菌菌株的实验室培养,还没有接近实现全面的
地球微生物组的生物合成潜力,以及细菌生物合成方法的根本变化,
因此,需要发现天然产物。因此,我的实验室一直在寻找方法
允许从环境样品中发现天然产物,而不需要菌株分离,
修为我建议从宏基因组文库中收获小分子的方法是
分为两大类:1)基于序列的宏基因组学,它依赖于DNA序列
与识别包含特定感兴趣基因的克隆的相似性,以及2)基于功能的宏基因组学,其
依赖于在表型分析中对单个eDNA克隆进行随机、无偏筛选来鉴定克隆
产生生物活性代谢物。使用基于序列的方法,我们可以询问宏基因组,
新的基因簇(即,新抗生素),以及编码临床相关抗生素同源物的簇
天然产物(即,提高临床上重要类别的抗生素的效用)。我们的功能筛选
研究将集中于开发用于创建富含天然高分子的宏基因组文库的方法。
产生基因簇,以促进更有效地筛选新型抗生素。对于本提案,我们将使用
我们现有的管道和改进的协议,因为他们上线,以确定新的天然产品,
提高了对抗生素抗性细菌病原体的活性。毫无疑问,我们才刚刚开始
隐藏在环境细菌基因组中的表面。这里的工作量将大大增加
获取隐藏在环境中的天然产物,并最终产生一系列新颖的
天然抗生素具有更好地治疗抗生素耐药性细菌病原体的潜力。
!
项目成果
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{{ truncateString('SEAN F BRADY', 18)}}的其他基金
Discovery and characterization of synthetic bioinformatic natural product anticancer agents
合成生物信息天然产物抗癌剂的发现和表征
- 批准号:
10639302 - 财政年份:2023
- 资助金额:
$ 67.8万 - 项目类别:
Synthetic environmental peptide libraries as a source of novel antibiotics
合成环境肽库作为新型抗生素的来源
- 批准号:
10394993 - 财政年份:2019
- 资助金额:
$ 67.8万 - 项目类别:
Synthetic environmental peptide libraries as a source of novel antibiotics
合成环境肽库作为新型抗生素的来源
- 批准号:
10613900 - 财政年份:2019
- 资助金额:
$ 67.8万 - 项目类别:
Discovery of GPCR-active natural products and their biosynthetic genes from the human associated bacteria
从人类相关细菌中发现具有 GPCR 活性的天然产物及其生物合成基因
- 批准号:
10229230 - 财政年份:2017
- 资助金额:
$ 67.8万 - 项目类别:
Discovery of Antibiotics from Soil Microbiomes Using Metagenomics
利用宏基因组学从土壤微生物组中发现抗生素
- 批准号:
10552394 - 财政年份:2017
- 资助金额:
$ 67.8万 - 项目类别:
Discovery of GPCR-active natural products and their biosynthetic genes from the human associated bacteria
从人类相关细菌中发现具有 GPCR 活性的天然产物及其生物合成基因
- 批准号:
10198774 - 财政年份:2017
- 资助金额:
$ 67.8万 - 项目类别:
Development and application of a functional metagenomic antibiotic discovery pipeline
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- 批准号:
9123633 - 财政年份:2015
- 资助金额:
$ 67.8万 - 项目类别:
Development and application of a functional metagenomic antibiotic discovery pipeline
功能性宏基因组抗生素发现管道的开发和应用
- 批准号:
8932426 - 财政年份:2015
- 资助金额:
$ 67.8万 - 项目类别:
A minimally invasive synthetic bio-driven approach for natural products discovery
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- 批准号:
9102130 - 财政年份:2015
- 资助金额:
$ 67.8万 - 项目类别:
A minimally invasive synthetic bio-driven approach for natural products discovery
用于天然产物发现的微创合成生物驱动方法
- 批准号:
8867550 - 财政年份:2015
- 资助金额:
$ 67.8万 - 项目类别:
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