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Redefining Fermentation Parameters in Natural Products Drug Discovery

重新定义天然产物药物发现中的发酵参数

基本信息

批准号：
10689269
负责人：
Anne Marie Casper
金额：
$ 15万
依托单位：
EASTERN MICHIGAN UNIVERSITY
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：
2022-08-23 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10689269
关键词：
Acceleration Achievement Agar Antibiotic Resistance Antibiotics Antimicrobial Effect Antimicrobial Resistance Area Bacterial Antibiotic Resistance Bacterial Genome Carbon Cesarean section Cessation of life Chemicals Chemotherapy-Oncologic Procedure Coculture Techniques Collection Communities Complex Data Disasters Effectiveness Exposure to Face Fermentation Future Gene Cluster Genome Genomics Individual Infection Intervention Lead Medical Metagenomics Methods Michigan Microbe Modern Medicine Modernization Molecular Natural Product Drug Natural Products Natural Products Chemistry Nature New Drug Approvals Nutrient Operative Surgical Procedures Organism Outcome Pathway Analysis Physiological Planet Earth Play Polysaccharides Procedures Process Production Property Public Health Reporting Reproducibility Research Scheme Self-Injurious Behavior Soil Source Students Superbug Techniques Technology Testing Therapeutic Time Training United States Universities Work antimicrobial cancer therapy drug candidate drug discovery global health emergency hip replacement arthroplasty metabolomics microbial microbial community microorganism natural antimicrobial novel novel antibiotic class pathogen priority pathogen programs scaffold screening transplantation medicine undergraduate research experience undergraduate student virtual

项目摘要

PROJECT SUMMARY The discovery of antibiotics from soil microbes is widely regarded as one of the most significant achievements in modern medicine, enabling many important medical procedures including surgery and cancer chemotherapy. However, antibiotic resistance is approaching such a critical level that we are facing an eminent public health disaster where many significant medical advancements may no longer be possible. There is an urgent need to develop and/or discover novel classes of antibiotics, especially antibiotics that are active against high-priority Gram-negative pathogens. Natural products have served as the scaffold for the vast majority of our current antibiotics, and recent advances in genomics, metagenomics, and metabolomics clearly indicate that there is still a vast wealth of biosynthetic potential encoded in bacterial genomes that could produce novel antibiotics. Unfortunately, identifying a novel biosynthetic gene clusters (BGCs) in a genome provides us with very little information about the chemical nature of the natural product it might produce. Thus, the field of natural product discovery, and consequently the field of antibiotic discovery, faces two major obstacles: how do we quickly and efficiently identify strains that have the potential to produce desirable novel compounds from “silent” BGCs and then how do we consistently induce the expression of these BGCs to characterize the compounds they produce. The induction of silent BGCs that produce antibiotics is likely context or community dependent, especially given the self-harming effects of antimicrobial compounds. Our previous work has validated a method for identifying microbes that produce antimicrobial compounds from silent BGCs, and this proposal describes methods for optimizing single- and mixed-culture fermentation conditions to consistently produce these compounds. In the research aims, we propose two complementary approaches to develop reproducible and scalable fermentation conditions that can broadly stimulate silent antibiotic production, which is often a rate limiting step in the field of natural products chemistry. Aim 1 will expand on our observations that microbes increase the production of antimicrobial compounds when grown in otherwise nutrient-limited media where complex polysaccharides are their dominant carbon source. Aim 2 will use co-culture to manipulate microbial physiological prior to fermentation. We expect that our optimized culture conditions will enable us to obtain natural product extracts that contain sufficient compound for feature-based molecular networking (FBMN) analyses to dereplicate antimicrobial compounds prior to activity-guided purification and structural elucidation of bioactive compounds (Aim 3).

项目概要从土壤微生物中发现抗生素被广泛认为是最重要的成就之一在现代医学中，使许多重要的医疗程序成为可能，包括手术和癌症化疗。然而，抗生素耐药性已接近临界水平，我们正面临着严峻的挑战。公共卫生灾难，许多重大的医疗进步可能不再可能。有一个迫切需要开发和/或发现新型抗生素，特别是活性抗生素针对高优先级革兰氏阴性病原体。天然产品已成为广大我们目前的大多数抗生素以及基因组学、宏基因组学和代谢组学的最新进展清楚地表明表明细菌基因组中仍然编码有大量的生物合成潜力，可以生产新型抗生素。不幸的是，在基因组中识别出一种新的生物合成基因簇（BGC）为我们提供的有关其可能产生的天然产物的化学性质的信息非常少。因此，天然产物发现领域以及抗生素发现领域面临着两个主要问题障碍：我们如何快速有效地识别有潜力产生理想小说的菌株来自“沉默”BGC 的化合物，然后我们如何持续诱导这些 BGC 的表达表征它们产生的化合物。产生抗生素的沉默 BGC 的诱导很可能取决于环境或社区，特别是考虑到抗菌化合物的自残作用。我们的之前的工作已经验证了一种识别产生抗菌化合物的微生物的方法沉默 BGC，该提案描述了优化单一和混合培养物发酵的方法持续生产这些化合物的条件。在研究目标中，我们提出了两个互补的开发可重复和可扩展的发酵条件的方法，可以广泛刺激沉默抗生素生产，这通常是天然产物化学领域的限速步骤。目标1将扩展我们的观察结果，即微生物在生长环境中会增加抗菌化合物的产生否则营养有限的培养基，其中复杂的多糖是其主要碳源。目标2将在发酵前使用共培养来操纵微生物生理学。我们期望我们优化的文化条件将使我们能够获得含有足够化合物的天然产物提取物，用于基于特征的分子网络 (FBMN) 分析可在活动引导之前消除抗菌化合物的重复生物活性化合物的纯化和结构阐明（目标 3）。