Genomics-Assisted Antibiotic Discovery from Unprecedented Microbes of the Great Salt Lake

基因组学辅助从大盐湖前所未有的微生物中发现抗生素

• 批准号: 10298732
• 负责人: Jaclyn Marie Winter
• 金额: $ 65.59万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10298732
• 关键词: Acinetobacter baumannii; Age; American; Americas; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Back; Bacteria; Bacterial Infections; Biochemical; Biochemistry; Bioinformatics; Biological; Biomedical Engineering; Cell physiology; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemical Agents; Chemicals; Cities; Clinical; Cluster Analysis; Coculture Techniques; Coupled; Data; Development; Disease; Drug resistance; ESKAPE pathogens; Enterobacter; Enterococcus faecium; Environment; Epigenetic Process; Escherichia coli; Essential Genes; Exhibits; FDA approved; Fermentation; Gene Cluster; Genome; Genomics; Health; Health Care Costs; Healthcare; High Pressure Liquid Chromatography; Human; Human Cell Line; Infection; Investigation; Klebsiella pneumoniae; Left; Libraries; Mass Spectrum Analysis; Methods; Microbe; Mining; Modification; Molecular; Molecular Target; Multi-Drug Resistance; Natural Products; Natural Products Chemistry; Nature; Nosocomial Infections; Oceans; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Play; Pseudomonas aeruginosa; Recombinants; Resistance; Resources; Role; Saline; Sea; Seawater; Site; Sodium Chloride; Soil; Source; Staphylococcus aureus; Structure; Toxic effect; Universities; Utah; Water; antimicrobial; antimicrobial drug; base; clinically significant; combat; drug discovery; drug resource; innovation; microbial; microorganism; novel; pathogenic bacteria; pressure; quorum sensing; resistance mechanism; scaffold; screening; small molecule; social; tool

PROJECT SUMMARY With antibiotic resistance mechanisms spreading rapidly among disease-causing bacteria, our ability to treat common infections is becoming increasingly difficult. To combat resistance, we desperately need new antibiotic agents possessing novel modes of action. Natural products, also called secondary metabolites, are small molecules produced in nature. Secondary metabolites play pivotal roles in many cellular processes and represent some of the most important pharmaceutical agents in human health care. This especially holds true in the antibiotic arena as a majority of the clinically prescribed antibiotics are natural products or derivatives thereof and have been isolated primarily from soil-dwelling bacteria. In recognition that microorganisms have been the most prolific source of new antibiotics, this project turns back to Nature to exploit the completely unexplored hypersaline microbes in the Great Salt Lake as a resource for drug discovery. Our observations are that environmental pressures influence the structural diversity of compounds produced in Nature and microorganisms thriving in extreme environments often produce chemical agents not observed in their terrestrial counterparts. The Great Salt Lake, also recognized as “America's Dead Sea”, is an endorheic (fully isolated) hypersaline lake located near the University of Utah in Salt Lake City, Utah. While seawater has an average salinity of ~3.3%, the Great Salt Lake ranges between 8-28%. Our preliminary data demonstrate that the unexplored hypersaline microorganisms of the Great Salt Lake possess antimicrobial activity against Gram-negative and Gram-positive bacterial pathogens, produce metabolites containing molecular scaffolds never before observed, and their genomes contain unprecedented biosynthetic machinery. Thus, these microbes serve as an ideal resource for the discovery of new antimicrobial agents possessing novel modes of action. To access and develop these agents, we have developed an integrated project that will leverage the strengths of our collaborative team including expertise in natural products isolation and structural elucidation, microbial biochemistry, genome mining, bioinformatics and bioengineering of recombinant natural products. From this project, unique antibiotic agents can be discovered along with information defining their biosynthetic pathways, their molecular targets, and likely other mechanisms of drug resistance. To exploit this novel resource, our specific aims will focus on: 1) Creating a hypersaline microbial library from sediment collected from the Great Salt Lake and screening the isolates using innovative methods for antimicrobial activity; 2) Identifying and validating new antibiotic agents using chemical and molecular networks; and 3) Identifying the biosynthetic machinery and molecular targets of the newly discovery antibiotic agents using genomic and bioinformatic approaches.

项目摘要 随着抗生素耐药性机制在引起疾病的细菌之间迅速扩散，我们的治疗能力 常见的感染变得越来越困难。为了抵抗抵抗，我们迫切需要新的抗生素 具有新型作用方式的代理商。天然产品，也称为次生代谢产物，很小 自然产生的分子。次生代谢产物在许多细胞过程中起关键作用，并且 代表人类医疗保健中一些最重要的药物。这尤其存在 抗生素竞技场是大多数临床处方抗生素是天然产品或其衍生物 并主要是从土壤居民细菌中分离出来的。认识到微生物一直是 最多产的新抗生素来源，该项目转向自然来利用完全出乎意料的 大盐湖中的高盐微生物作为药物发现的资源。我们的观察是 环境压力影响自然和微生物产生的化合物的结构多样性 在极端环境中蓬勃发展通常会产生在其陆地对应物中未观察到的化学药品。 大盐湖（Great Salt Lake）也被认为是“美国的死海” 位于犹他州盐湖城的犹他大学附近。尽管海水的平均盐度约为3.3％，但 大盐湖在8-28％之间。我们的初步数据表明意外的催眠盐 大盐湖电势抗菌活性的微生物针对革兰氏阴性和革兰氏阳性 细菌病原体，产生含有前所未有的分子支架的代谢产物，它们 基因组含有前所未有的生物合成机械。那就是这些微生物是 发现具有新型作用模式的新抗菌剂。访问和开发这些 代理商，我们开发了一个集成项目，该项目将利用我们的协作团队的优势 包括天然产品隔离和结构阐明方面的专业知识，微生物生物化学，基因组 重组天然产品的采矿，生物信息学和生物工程。从这个项目中，独特的抗生素 可以发现代理以及定义其生物合成途径的信息，即它们的分子靶标， 以及可能的其他耐药性机制。为了利用这一新型资源，我们的具体目标将重点关注： 1）从大盐湖收集的沉积物中创建一个高盐微生物库，并筛选 使用创新方法进行抗菌活性的分离株； 2）识别和验证新的抗生素剂 使用化学和分子网络； 3）确定生物合成机械和分子靶标的 使用基因组和生物信息学方法的新发现抗生素。