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
基本信息
- 批准号:10359678
- 负责人:
- 金额:$ 77.02万
- 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:2019-03-25 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:Actinobacteria classAddressAnalytical ChemistryAnti-Bacterial AgentsAntibioticsAntifungal AgentsBacillus subtilisBioinformaticsBiologicalBiological AssayCatalogsChemicalsCloningCollaborationsCommunitiesComputer softwareCustomDataDrug IndustryDrug resistanceEnsureEscherichia coliFamily memberFirmicutesFutureGene ClusterGeneticGenomeGoalsIndividualIndustrializationKnowledgeLassoLettersMalariaMass Spectrum AnalysisMethodsMiningModernizationModificationMultidimensional NMR TechniquesNamesNatural Product DrugNatural ProductsPathway interactionsPeptidesPharmaceutical PreparationsProductionReportingRibosomesSamplingSourceStreptomycesStructureTherapeuticTuberculosisantimicrobialbasedesigndrug discoveryexperiencemethod developmentneglected tropical diseasesnovelnovel therapeuticsopen innovationpathogenic bacteriapeptide structureprogramsscaffoldscale upsuccesssynthetic biologytool
项目摘要
PROJECT SUMMARY/ABSTRACT
Natural products have been by far the most prolific source of chemical matter that has been developed into
modern antibacterial and antifungal drugs by the pharmaceutical industry. However, despite the pressing need
for new drugs to address the alarming rise of drug resistance, especially amongst Gram-negative bacterial
pathogens, the rate of discovering natural products has diminished. In this R01 project, we propose to develop
a scalable platform to produce novel ribosomal natural products, i.e. ribosomally synthesized and
posttranslationally modified peptides (RiPPs). With more than two dozen distinct classes of RiPPs identified thus
far, and several new classes being identified each year, RiPPs represent a promising addition to the antibacterial
and antifungal drugs biosynthesized by polyketide and non-ribosomal pathways yet they remain vastly
underexploited by comparison. Specifically, we will integrate bioinformatics, synthetic biology, and analytical
chemistry tools to develop a Fully Automated, Scalable, and high-Throughput (FAST) pipeline for the discovery
and characterization of one thousand novel RiPPs from uncharacterized RiPP biosynthetic gene clusters (BGCs)
of both known and unknown classes. The resultant novel RiPPs will be assayed for their antibacterial and
antifungal activities as well as other related biological activities towards neglected and tropical diseases
(tuberculosis and malaria) through a collaboration with Lilly's Open Innovation Drug Discovery Program
(openinnovation.lilly.com). This project represents the first large-scale attempt at unlocking the potential of RiPPs
as a source of new antibacterial and antifungal drugs, which based on their genetic compactness, are ideally
suited for the synthetic biology methods and goals described within. For this project, we propose three
interrelated but independently achievable specific aims. Aim 1 will discover novel RiPPs from known classes
using lower throughput methods. Aim 2 will scale up the discovery of novel RiPPs from known classes using the
FAST pipeline. Aim 3 will predict and produce RiPPs from classes that have not yet been reported, which will
ensure a variety of novel natural product scaffolds. Success in the overall project will change the paradigm for
natural product discovery and will potentially have a profound impact on the pharmaceutical industry.
项目总结/摘要
天然产物是迄今为止最丰富的化学物质来源,
现代抗细菌和抗真菌药物。然而,尽管迫切需要
新的药物来解决令人担忧的耐药性上升,特别是在革兰氏阴性细菌中,
病原体,发现天然产品的速度已经下降。在R 01项目中,我们建议开发
一个可扩展的平台,以产生新的核糖体天然产物,即核糖体合成的,
后修饰肽(RIPPs)。有二十多个不同类别的RIPP被确定,
到目前为止,每年都有几个新的类别被确定,RIPPs代表了一个有希望的抗菌剂
以及通过聚酮化合物和非核糖体途径生物合成的抗真菌药物,
相比之下,开发不足。具体来说,我们将整合生物信息学,合成生物学和分析生物学。
化学工具来开发全自动、可扩展和高吞吐量(FAST)管道,
和表征来自未表征的RiPP生物合成基因簇(BGC)的一千种新型RiPP
已知和未知的类。将测定所得的新型RIPP的抗菌性和生物相容性。
抗真菌活性以及针对被忽视疾病和热带疾病的其他相关生物活性
(结核病和疟疾)通过与礼来公司的开放创新药物发现计划合作,
(openinnovation.lilly.com)中找到。该项目代表了释放RIPP潜力的首次大规模尝试
作为新的抗细菌和抗真菌药物的来源,基于它们的遗传紧凑性,
适用于合成生物学方法和目标内所述。在这个项目中,我们提出三个
相互关联但独立可实现的具体目标。目标1将从已知类中发现新的RIPP
使用较低吞吐量的方法。目标2将使用
快速管道。目标3将从尚未报告的类别中预测和产生RIPP,这将
保证了多种新型天然产物支架。整个项目的成功将改变
天然产物的发现,并可能对制药行业产生深远的影响。
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 }}
Douglas Alan Mitchell其他文献
Douglas Alan Mitchell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('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:
$ 77.02万 - 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:
$ 77.02万 - 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:
$ 77.02万 - 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:
$ 77.02万 - 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:
$ 77.02万 - 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:
$ 77.02万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 77.02万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 77.02万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 77.02万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 77.02万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 77.02万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 77.02万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 77.02万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 77.02万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 77.02万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 77.02万 - 项目类别:
Research Grant