An LCMS-guided bioanalytical approach for rational natural product library design and optimization
LCMS 引导的生物分析方法,用于合理的天然产物库设计和优化
基本信息
- 批准号:10697396
- 负责人:
- 金额:$ 7.06万
- 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:2022-09-05 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAccountingAddressAffectAlternariaAmericanBiologicalBreathingChemicalsCoculture TechniquesCollectionComplexDataDiseaseDiversity LibraryEnsureEnvironmentEpidemicGenerationsHabitsIndividualLeadLibrariesLiquid ChromatographyMethodologyMethodsNatural ProductsNatureOklahomaPersonsPharmaceutical PreparationsPharmacologic SubstancePovertyProductionPublic HealthRandomizedRare DiseasesReportingRiskRunningSamplingSignal TransductionSoilSourceStressSystemTestingTrichodermaUniversitiesValidationWorkcitizen scienceclinical translationcostdesigndrug developmentdrug discoverydrug resourceemerging pathogenevidence basefungushigh throughput screeningliquid chromatography mass spectrometrymetabolomicsmicrobialnovelnovel strategiesprogramsquorum sensingrational designscaffoldsingle moleculesmall moleculesmall molecule librariessuccesstandem mass spectrometry
项目摘要
Project Summary/Abstract
Natural products are a mainstay of drug discovery, accounting for up to 50% of approved drugs either as
direct natural molecules or as inspiration for synthetic molecules. High-throughput screening of compound
libraries is a common starting point for drug development campaigns. The quality of these libraries is therefore
a key determinant of high-throughput screening campaign success. Natural product compound library design is
particularly challenging given redundancies in natural product production between isolates and greater costs of
compound production and isolation. Evidence-based and scientifically rigorous methods to optimize
natural product library design are therefore urgently required. In MPIs’ previous work, they demonstrated
using the example of the fungus Alternaria that liquid chromatography-tandem mass spectrometry (LC-
MS/MS)-based analysis of fungal extracts could reveal the minimal number of extracts to include in a chemical
library, to achieve saturation of chemical diversity. Strikingly, this number could be as small as 39 isolate
extracts, depending on the Alternaria clade. It is now necessary to demonstrate the broader utility of this
bioanalytical approach, to the significant biological problem of high-throughput screening natural product
chemical library design. In addition, the high-throughput nature of our approach enables the systematic and
unbiased assessment of different natural product diversification approaches on elicited chemical diversity. Our
proposal builds on MPI’s extensive expertise in metabolomics and small molecule characterization and natural
product analysis. In addition, it is enabled by the MPI’s access to the large collection of fungal isolates from the
University of Oklahoma Citizen Science Soil Collection Program. This collection currently totals >78,000
isolates from 893 fungal genera. Our central hypothesis is that our untargeted metabolomics method can
be applied to generate specific rules of natural product library design and provide evidence to prove or
disprove current dogma governing natural product library design. We will focus on three common library
design approaches, in three independent aims. Aim 1 will focus on using our approach to demonstrate that
comparable chemical diversity can be obtained from focused, rationally-designed natural product libraries,
compared to random serendipitous discovery. Aim 2 will systematically assess the impact of co-culture on
elicited chemical diversity, comparing sympatric vs allopatric co-culture systems. Aim 3 will systematically
quantify the impact of environment-mimicking culture conditions such as soil or bacterial-derived signals, on
elicited chemical diversity. Overall, our results will lead to validation of a new approach for rational natural
product library design, with major implications for drug development.
项目总结/摘要
天然产品是药物发现的支柱,占批准药物的50%,
直接天然分子或作为合成分子的灵感。化合物的高通量筛选
图书馆是药物开发运动的共同起点。因此,这些库的质量
高通量筛选活动成功的关键决定因素。天然产物化合物库设计
考虑到分离物之间天然产物生产的冗余和更高的生产成本,
化合物的制备和分离。基于证据和科学严谨的方法来优化
因此,迫切需要天然产物库设计。在MPI以前的工作中,他们证明了
以链格孢属真菌为例,采用液相色谱-串联质谱法(LC-MS)
基于MS/MS)的真菌提取物分析可以揭示化学品中包含的提取物的最小数量
图书馆,以实现化学多样性的饱和。引人注目的是,这个数字可能小到39个分离物
提取物,取决于链格孢属分支。现在有必要证明这一点的更广泛效用
生物分析方法,高通量筛选天然产物的重大生物学问题
化学库设计此外,我们的方法的高通量性质使得能够系统和
对不同的天然产品多样化方法引起的化学多样性进行无偏见的评估。我们
该提案建立在MPI在代谢组学和小分子表征以及天然药物方面的广泛专业知识基础上。
产品分析此外,它是由MPI的访问,以大量收集的真菌分离物,从
俄克拉荷马州大学公民科学土壤收集计划。目前,这一数字已超过78,000。
893个真菌属。我们的中心假设是,我们的非靶向代谢组学方法可以
应用于生成自然产品库设计的具体规则,并提供证据证明或
反驳当前自然产品库设计的教条。我们将重点介绍三个常见的库
设计方法,在三个独立的目标。目标1将重点关注使用我们的方法来证明,
可以从集中的、合理设计的天然产物库中获得可比较的化学多样性,
与偶然的发现相比目标2将系统地评估共同培养对
引起化学多样性,比较同域与异域共培养系统。目标3将系统地
量化模拟环境的培养条件,如土壤或细菌来源的信号,
引发了化学多样性总的来说,我们的研究结果将导致一种新的方法,合理的自然验证
产品库设计,对药物开发有重大影响。
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)
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Robert Henry Cichewicz其他文献
Robert Henry Cichewicz的其他文献
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{{ truncateString('Robert Henry Cichewicz', 18)}}的其他基金
An LCMS-guided bioanalytical approach for rational natural product library design and optimization
LCMS 引导的生物分析方法,用于合理的天然产物库设计和优化
- 批准号:
10418425 - 财政年份:2022
- 资助金额:
$ 7.06万 - 项目类别:
Fungal natural products targeting antimicrobial resistant Mycoplasma genitalium
针对抗菌药物耐药性生殖支原体的真菌天然产品
- 批准号:
10308114 - 财政年份:2020
- 资助金额:
$ 7.06万 - 项目类别:
Exploiting Fungal Natural Products to Discover Novel Scaffolds That Inhibit Dormant and Drug-Resistant TB
利用真菌天然产物发现抑制休眠和耐药结核病的新型支架
- 批准号:
9316820 - 财政年份:2017
- 资助金额:
$ 7.06万 - 项目类别:
Procuring Native Natural Product Producers by In Situ Chimera Assembly
通过原位嵌合体组装采购天然产物生产商
- 批准号:
9065487 - 财政年份:2015
- 资助金额:
$ 7.06万 - 项目类别:
Early Stage Discovery of Natural Products Targeting Anaerobic Protozoal Pathogen
针对厌氧原虫病原体的天然产物的早期发现
- 批准号:
9088344 - 财政年份:2015
- 资助金额:
$ 7.06万 - 项目类别:
Early Stage Discovery of Natural Products Targeting Anaerobic Protozoal Pathogen
针对厌氧原虫病原体的天然产物的早期发现
- 批准号:
9480206 - 财政年份:2015
- 资助金额:
$ 7.06万 - 项目类别:
Sourcing Bioactive Secondary Metabolites from Great Lakes Fungi
从五大湖真菌中采购生物活性次生代谢物
- 批准号:
9054134 - 财政年份:2014
- 资助金额:
$ 7.06万 - 项目类别:
Sourcing Bioactive Secondary Metabolites from Great Lakes Fungi
从五大湖真菌中采购生物活性次生代谢物
- 批准号:
8697723 - 财政年份:2014
- 资助金额:
$ 7.06万 - 项目类别:
New Leads for Triple Negative Breast Cancer from Diverse Natural Sources
来自不同天然来源的三阴性乳腺癌的新线索
- 批准号:
8761726 - 财政年份:2014
- 资助金额:
$ 7.06万 - 项目类别:
Sourcing Bioactive Secondary Metabolites from Great Lakes Fungi
从五大湖真菌中采购生物活性次生代谢物
- 批准号:
9296148 - 财政年份:2014
- 资助金额:
$ 7.06万 - 项目类别:
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