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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).

项目总结