Capturing evolved small molecule natural product chemical space
捕获进化的小分子天然产物化学空间
基本信息
- 批准号:RGPIN-2014-05577
- 负责人:
- 金额:$ 3.86万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Discovery Grants Program - Individual
- 财政年份:2015
- 资助国家:加拿大
- 起止时间:2015-01-01 至 2016-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Natural small chemicals, natural products, exhibit a wide spectrum of activity with significant industrial and medicinal value. Within their natural context these molecules have been evolved as a form of communication between cells and to assist the life of the organisms that produce them. Their evolved status is evident in the selectivity to their bio-molecular targets and demonstrated impact on cells. Biosynthetic machinery leading to natural products of different categories (e.g. terpenes, polyketides, nonribosomal peptides) are now well appreciated and their codes have been cracked such that the connection between genetic instruction and end product small molecules is appreciated. The advent of genomic sequencing of natural product sources have opened up a large cache of new natural products that await discovery and evaluation for their industrial and pharmaceutical use. The purpose of the proposed research program will be to design and implement powerful new tools and strategies to enable the rapid connection of genomic information to small molecule natural products. The propose research program will seek to develop powerful strategies to selectively identify and capture these evolved natural products a reality for testing. Genomic sequencing of proven antibiotic producers and numerous poorly studied microorganisms has produced a deep view of their metabolic capability. These genomically-envisioned cohort of microbial natural products, or what can be referred to as ‘unknown known’ natural products, are increasing with the continued advance of microbial genome sequencing with next-generation sequencing approaches. To selectively identify these unknown known molecules, without first re-investigating (re-isolating) the known natural products will demand cutting-edge strategies to target them within the complex metabolomes in which they are found. Technologies will need to be sensitive enough to identify them when they are present in trace amounts and drive the production of these unknown agents with they are revealed in vanishing quantities. The proposed program will create powerful new platform technologies to selectively identify polyketide and nonribosomal peptide natural products by integrating numerous forms of ‘omic’ information with chemoinformatic and bioinformatic data processing strategies in conjunction with modern analytical instruments. The program will build significantly from the current NSERC-supported program that has produced several innovative works in developing an informatic search for natural products (iSNAP). Importantly this renewal will focus on the deployment of these technologies to selectively isolate new bioactive polyketide and nonribosomal peptides that considers the chemical ecology and systems in which they are found. I wish to advance the hypothesis, that the previous early golden age of antibiotic discovery driven by bioactivity guided activities revealed only a small fraction of the antibiotics that have been naturally evolved. My laboratory will interrogate the early organisms (producers of known antibiotics) that lead to the seminal discoveries in early antibiotic discovery, but instead of randomly assessing these organisms we will first obtain genomic sequences of them using instrumentation supported by my laboratories new CFI LOF infrastructure (genomic sequencers and mass spectrometers) and then leverage that genomic sequence to predict and selectively mine for known unknown natural products. Once these molecules are isolated we will then query their biological activities and specifically whether these unknown known molecules exhibit potent antimicrobial activities to drug resistant pathogenic bacteria and their collective activities (synergies).
天然小分子化合物,天然产物,具有广泛的活性,具有重要的工业和药用价值。在它们的自然环境中,这些分子已经进化为细胞之间的一种交流形式,并帮助产生它们的生物体的生命。它们的进化状态在对其生物分子靶标的选择性和对细胞的影响方面是显而易见的。生物合成机制导致不同类别的天然产物(如萜烯,聚酮化合物,非核糖体肽)现在得到了很好的理解,他们的代码已经被破解,使遗传指令和最终产物小分子之间的联系得到理解。天然产物来源的基因组测序的出现已经打开了大量等待发现和评估其工业和制药用途的新天然产物的缓存。该研究计划的目的是设计和实施强大的新工具和策略,使基因组信息与小分子天然产物快速连接。拟议的研究计划将寻求制定强有力的战略,以选择性地识别和捕获这些进化的天然产品,以进行测试。 已证实的抗生素生产者和许多研究不足的微生物的基因组测序已经产生了对其代谢能力的深入了解。这些基因组学上设想的微生物天然产物的群组,或可以被称为“未知已知”的天然产物,随着利用下一代测序方法的微生物基因组测序的持续进展而增加。为了选择性地识别这些未知的已知分子,而不首先重新研究(重新分离)已知的天然产物,将需要尖端的策略,在发现它们的复杂代谢组中靶向它们。技术需要足够灵敏,以便在它们以痕量存在时识别它们,并在它们以消失的数量出现时驱动这些未知物质的生产。该计划将创建强大的新平台技术,通过将多种形式的“组学”信息与化学信息学和生物信息学数据处理策略结合现代分析仪器,选择性地识别聚酮化合物和非核糖体肽天然产物。该计划将从目前的NSERC支持的计划中显著构建,该计划在开发天然产品信息搜索(iSNAP)方面产生了几项创新工作。重要的是,这次更新将集中在这些技术的部署,以选择性地分离新的生物活性聚酮和非核糖体肽,考虑到化学生态和系统中,他们被发现。我希望推进的假设,即以前的早期黄金时代的抗生素发现的生物活性导向的活动,揭示了只有一小部分的抗生素,已自然演变。我的实验室会研究早期的生物体(已知抗生素的生产商),导致了早期抗生素发现的开创性发现,但我们不会随机评估这些生物,而是首先使用由我的实验室新的CFI LOF基础设施支持的仪器获得它们的基因组序列(基因组测序仪和质谱仪),然后利用基因组序列来预测和选择性地挖掘已知的未知天然产物。一旦这些分子被分离,我们将查询它们的生物活性,特别是这些未知的已知分子是否对耐药病原菌及其集体活性(协同作用)表现出有效的抗微生物活性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Magarvey, Nathan其他文献
Magarvey, Nathan的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Magarvey, Nathan', 18)}}的其他基金
Capturing evolved small molecule natural product chemical space
捕获进化的小分子天然产物化学空间
- 批准号:
RGPIN-2014-05577 - 财政年份:2018
- 资助金额:
$ 3.86万 - 项目类别:
Discovery Grants Program - Individual
Capturing evolved small molecule natural product chemical space
捕获进化的小分子天然产物化学空间
- 批准号:
RGPIN-2014-05577 - 财政年份:2017
- 资助金额:
$ 3.86万 - 项目类别:
Discovery Grants Program - Individual
Capturing evolved small molecule natural product chemical space
捕获进化的小分子天然产物化学空间
- 批准号:
RGPIN-2014-05577 - 财政年份:2016
- 资助金额:
$ 3.86万 - 项目类别:
Discovery Grants Program - Individual
Capturing evolved small molecule natural product chemical space
捕获进化的小分子天然产物化学空间
- 批准号:
RGPIN-2014-05577 - 财政年份:2014
- 资助金额:
$ 3.86万 - 项目类别:
Discovery Grants Program - Individual
Molecular signals of multicellularity
多细胞性的分子信号
- 批准号:
371576-2009 - 财政年份:2013
- 资助金额:
$ 3.86万 - 项目类别:
Discovery Grants Program - Individual
Molecular signals of multicellularity
多细胞性的分子信号
- 批准号:
371576-2009 - 财政年份:2012
- 资助金额:
$ 3.86万 - 项目类别:
Discovery Grants Program - Individual
Molecular signals of multicellularity
多细胞性的分子信号
- 批准号:
371576-2009 - 财政年份:2011
- 资助金额:
$ 3.86万 - 项目类别:
Discovery Grants Program - Individual
Mining marine microbial mats for bioactive secondary metabolites
开采海洋微生物垫以获得生物活性次生代谢物
- 批准号:
385235-2009 - 财政年份:2011
- 资助金额:
$ 3.86万 - 项目类别:
Strategic Projects - Group
Molecular signals of multicellularity
多细胞性的分子信号
- 批准号:
371576-2009 - 财政年份:2010
- 资助金额:
$ 3.86万 - 项目类别:
Discovery Grants Program - Individual
相似海外基金
Mechanism of Resistance Avoidance in Synthetically Evolved Antibacterial Peptides
合成进化抗菌肽避免耐药性的机制
- 批准号:
10412134 - 财政年份:2021
- 资助金额:
$ 3.86万 - 项目类别:
Mechanism of Resistance Avoidance in Synthetically Evolved Antibacterial Peptides
合成进化抗菌肽避免耐药性的机制
- 批准号:
10308818 - 财政年份:2021
- 资助金额:
$ 3.86万 - 项目类别:
Capturing evolved small molecule natural product chemical space
捕获进化的小分子天然产物化学空间
- 批准号:
RGPIN-2014-05577 - 财政年份:2018
- 资助金额:
$ 3.86万 - 项目类别:
Discovery Grants Program - Individual
Capturing evolved small molecule natural product chemical space
捕获进化的小分子天然产物化学空间
- 批准号:
RGPIN-2014-05577 - 财政年份:2017
- 资助金额:
$ 3.86万 - 项目类别:
Discovery Grants Program - Individual
Capturing evolved small molecule natural product chemical space
捕获进化的小分子天然产物化学空间
- 批准号:
RGPIN-2014-05577 - 财政年份:2016
- 资助金额:
$ 3.86万 - 项目类别:
Discovery Grants Program - Individual
Capturing evolved small molecule natural product chemical space
捕获进化的小分子天然产物化学空间
- 批准号:
RGPIN-2014-05577 - 财政年份:2014
- 资助金额:
$ 3.86万 - 项目类别:
Discovery Grants Program - Individual
STRUCTURE, MECHANISM AND CATALYSIS IN EVOLVED RIBOZYME AND RNA VIRUSES
进化核酶和RNA病毒的结构、机制和催化
- 批准号:
8169930 - 财政年份:2010
- 资助金额:
$ 3.86万 - 项目类别:
STRUCTURE, MECHANISM AND CATALYSIS IN EVOLVED RIBOZYME AND RNA VIRUSES
进化核酶和RNA病毒的结构、机制和催化
- 批准号:
7954192 - 财政年份:2009
- 资助金额:
$ 3.86万 - 项目类别:
Targeting A-beta with evolved site-specific proteases
使用进化的位点特异性蛋白酶靶向 A-β
- 批准号:
7361795 - 财政年份:2008
- 资助金额:
$ 3.86万 - 项目类别:
STRUCTURE, MECHANISM AND CATALYSIS IN EVOLVED RIBOZYME AND RNA VIRUSES
进化核酶和RNA病毒的结构、机制和催化
- 批准号:
7721797 - 财政年份:2008
- 资助金额:
$ 3.86万 - 项目类别: