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

项目摘要 随着抗生素耐药性机制在致病细菌中迅速传播，我们治疗疾病的能力 普通感染变得越来越困难。为了对抗耐药性，我们迫切需要新的抗生素 具有新颖作用模式的药剂。天然产物，也称为次级代谢产物，体积很小 自然界中产生的分子。次级代谢产物在许多细胞过程中起着关键作用， 代表了人类保健中一些最重要的药剂。这尤其适用于 抗生素竞技场作为大多数临床处方抗生素是天然产物或其衍生物 主要从土壤细菌中分离出来。认识到微生物一直是 最多产的新抗生素来源，这个项目回到自然界，利用完全未开发的 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， 环境压力影响自然界和微生物产生的化合物的结构多样性 在极端环境中生长，往往会产生在陆地上看不到的化学制剂。 大盐湖，也被称为“美国的死海”，是一个内流（完全孤立）高盐度湖 位于犹他州湖城的犹他州大学附近。虽然海水的平均盐度约为3.3%， 大盐湖的比例在8- 28%之间。我们的初步数据表明， 大盐湖微生物对革兰氏阴性菌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， 基因组包含前所未有的生物合成机制。因此，这些微生物是一种理想的资源， 发现具有新作用模式的新型抗菌剂。为了获取和开发这些 代理商，我们已经开发了一个综合项目，将利用我们的协作团队的优势 包括天然产物分离和结构解析、微生物生物化学、基因组学 重组天然产物的开采、生物信息学和生物工程。从这个项目中，独特的抗生素 可以沿着定义其生物合成途径，其分子靶点， 以及其他可能的耐药性机制。为了开发这一新资源，我们的具体目标将集中在： 1)从大盐湖沉积物中建立高盐微生物文库并筛选高盐微生物 使用创新的方法进行抗菌活性的分离; 2）鉴定和验证新的抗生素制剂 使用化学和分子网络;和3）确定生物合成机制和分子靶标 利用基因组学和生物信息学方法发现的新抗生素制剂。

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.