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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要随着抗生素耐药机制在致病细菌中迅速传播，我们治疗的能力为了对抗耐药性，我们迫切需要新的抗生素。具有新颖作用方式的天然产物，也称为次级代谢物，是小的。自然界产生的分子在许多细胞过程中发挥着关键作用。代表了人类医疗保健中一些最重要的药剂，这尤其适用于。抗生素领域，因为大多数临床处方抗生素都是天然产物或其衍生物并主要从土壤细菌中分离出来。作为新抗生素最多产的来源，该项目回归自然，开发完全未开发的抗生素我们的观察结果是，大盐湖中的高盐微生物可以作为药物发现的资源。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繁衍生息通常会产生在其陆地盟友中未观察到的化学物质。大盐湖，也被称为“美国的死海”，是一个内流（完全孤立）的超盐湖位于犹他州盐湖城的犹他大学附近，虽然海水的平均盐度约为 3.3%，但我们的初步数据表明，大盐湖的盐度范围为 8-28%。大盐湖的微生物对革兰氏阴性和革兰氏阳性菌具有抗菌活性细菌病原体，产生含有以前从未观察到的分子支架的代谢物，及其基因组包含前所未有的生物合成机制，因此，这些微生物是理想的资源。发现具有新作用方式的新抗菌剂以获取和开发这些药物。代理，我们开发了一个综合项目，将利用我们协作团队的优势包括天然产物分离和结构解析、微生物生物化学、基因组方面的专业知识重组天然产物的挖掘、生物信息学和生物工程从这个项目中，独特的抗生素。可以发现药物以及定义其生物合成途径、分子靶标的信息，以及可能的其他耐药机制为了利用这种新资源，我们的具体目标将集中在： 1）利用从大盐湖收集的沉积物创建高盐微生物库并筛选使用创新方法进行抗菌活性分离；2) 识别和验证新的抗生素药物使用化学和分子网络；3) 识别生物合成机制和分子靶标使用基因组和生物信息学方法新发现的抗生素药物。