Microbial Ecology-Guided Discovery of Antibacterial Drugs

微生物生态学引导抗菌药物的发现

基本信息

批准号：
10446908
负责人：
Eric W Schmidt
金额：
$ 66.48万
依托单位：
UNIVERSITY OF UTAH
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：
2022-02-07 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10446908
关键词：
Acinetobacter Acinetobacter baumannii Animals Anti-Bacterial Agents Antibiotics Antimicrobial Resistance Bacteria Benign Biological Assay Biology Cecum Cells Cellulases Cellulose Chemicals Chemistry Clinical Communicable Diseases Consumption Data Digestion Distant Distel Drug resistance Eating Ecology Environment Evolution Genetic Genetic Engineering Genomics Gills Glucose Goals Health Human Investments Membrane Methods Microbe Modification Multi-Drug Resistance Multiple Bacterial Drug Resistance Natural Product Drug Natural Products Nutritional Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacologic Substance Physiology Problem Solving Process Production Property Research Resistance Role Science Sea Series Source Streptomyces System Technology Time Toxic effect Volatile Fatty Acids Water Wood material base chemical genetics chemical synthesis clinically relevant combat design drug development drug discovery experience experimental study gene cloning genetic analysis guided inquiry human pathogen improved in vivo interest microbial new technology novel novel therapeutics pathogen pathogenic bacteria pharmacokinetics and pharmacodynamics programs resistant strain scaffold small molecule symbiont virtual

项目摘要

Project Summary/Abstract Multidrug-resistant bacteria are an increasing health threat. Most new antibacterial agents are natural products that are made by bacteria, or their synthetic derivatives. This is because, over evolutionary time, bacteria gain the ability to synthesize small molecules that very selectively target essential processes in other bacteria. One problem in identifying good antibacterial agents that are relatively nontoxic to people is that early drug discovery assays cannot determine whether compounds are truly selective until well into the drug development process. There is no reason that randomly cultivated bacteria from the environment would produce chemicals that are benign in humans, yet lethal to competing bacteria. Finding those compounds, or improving existing compounds to minimize toxicity and improve antibacterial activity, requires a significant investment. Here, we propose to examine symbiotic bacteria that are compatible with animal physiology, and for which evolution favors the production of selective antibacterial agents. The bacteria are enriched within animal hosts, where they produce hundreds or perhaps thousands of small molecule natural products. One of the main ecological roles of the symbiotic bacteria is likely to clear other bacteria from the host. Proof-of-concept experiments demonstrate that the bacteria produce nontoxic compounds that very selectively target human pathogens, including some of the most lethal bacterial pathogens that infect humans. In this program, we will optimize identified, chemically novel antibacterial compounds by understanding their mechanisms of action and by investigating and improving their existing properties further through chemical synthesis. Further, we will continue to identify and characterize promising new antibacterial agents that are previously unknown to science. Our long-term goal is to provide a novel pipeline of new antibacterial agents to combat multidrug resistance.

项目摘要/摘要多药耐药细菌是日益增长的健康威胁。大多数新的抗菌剂是天然产品由细菌或其合成衍生物制成的。这是因为，在进化时，细菌会增加合成小分子的能力，这些分子非常有选择地靶向其他细菌的基本过程。一确定对人相对无毒的良好抗菌剂的问题是早期药物发现分析无法确定化合物在进入药物开发之前是否真正有选择性过程。没有理由从环境中随机培养的细菌会产生化学物质在人类中是良性的，但对竞争细菌而致命。找到这些化合物或改善现有可以最大程度地减少毒性并改善抗菌活性的化合物，需要大量投资。在这里，我们建议检查与动物生理兼容的共生细菌，并以此进化有利于选择性抗菌剂的产生。细菌在动物宿主中富集它们生产数百个或数千种小分子天然产品。主要生态之一共生细菌的作用可能从宿主那里清除其他细菌。概念验证实验证明细菌产生的无毒化合物非常有选择地靶向人类病原体，包括一些感染人类的最致命的细菌病原体。在此程序中，我们将优化通过理解其作用机制和通过通过化学合成进一步研究和改善其现有特性。此外，我们会的继续识别并表征有希望的新抗菌剂，这些抗菌剂以前未知科学。我们的长期目标是提供新的新抗菌剂管道，以对抗多药反抗。