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/文摘
项目成果
期刊论文数量(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:
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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
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- 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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