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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：
10418425
负责人：
Robert Henry Cichewicz
金额：
$ 35.89万
依托单位：
UNIVERSITY OF OKLAHOMA
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 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10418425
关键词：
Accounting Address Affect Alternaria American Biological Breathing Chemicals Coculture Techniques Collection Complex Data Disease Diversity Library Ensure Environment Epidemic Generations Habits Individual Lead Libraries Liquid Chromatography Methodology Methods Natural Products Nature Oklahoma Persons Pharmaceutical Preparations Pharmacologic Substance Poverty Production Public Health Randomized Rare Diseases Reporting Risk Running Sampling Signal Transduction Soil Source Stress System Testing Trichoderma Universities Validation Work base citizen science clinical translation cost design drug development drug discovery drug resource emerging pathogen evidence base fungus high throughput screening liquid chromatography mass spectrometry metabolomics microbial novel novel strategies programs quorum sensing rational design scaffold single molecule small molecule small molecule libraries success tandem 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