Isolating novel actinomycetes for antibiotic discovery

描述（由申请方提供）：耐药病原体引起的感染发生率增加，加上需要开发针对生物恐怖剂的抗菌对策，因此迫切需要开发新的两用抗生素。该项目的目标是开发新型广谱抗生素，从生物防御的角度出发，对包括鼠疫耶尔森氏菌和炭疽杆菌在内的关注细菌以及临床上重要的多重耐药细菌病原体具有活性，包括耐甲氧西林金黄色葡萄球菌（MRSA）、耐万古霉素肠球菌（VRE）、鲍曼不动杆菌、表达超广谱β-内酰胺酶（ESBL）的肠杆菌和铜绿假单胞菌。这一目标将通过应用一种新的培养方法来实现，该方法利用陷阱原位捕获以前未培养的放线菌，这是当今市场上大多数抗生素的来源。这些新的放线菌将被探索其产生新抗生素的能力。在这里，我们提出的数据表明，我们的原位陷阱的能力：1）有效地富集放线菌，2）选择不同的放线菌属比传统的微生物方法和3）分离放线菌物种，以前没有发现。在这个第一阶段的项目中，我们将把陷阱方法发展成一个药物开发管道，并根据从我们的陷阱衍生放线菌中鉴定出的抗菌化合物的独特性来评估这项技术的成功。本项目的具体目标是：目的1：为了评价通过NovoBiotic诱捕法分离的放线菌的新奇，我们将使用诱捕技术分离1000株新放线菌并鉴定这些菌种。目的2：从我们的1000个陷阱来源的放线菌中提取抗生素生产，并优先选择50个分离株进行分析化学分析。目的3：对本实验室分离的放线菌产生的抗菌物质进行去复制。第一阶段的成果将用于第二阶段，以开发开发两用抗生素所需的陷阱衍生放线菌的大规模培养、发酵、化学去复制。 公共卫生相关性：在社区和医院引起感染的细菌对现有抗生素的耐药性越来越强，因此迫切需要新的抗生素，以确保未来几年的公共卫生。该项目的目的是采用新技术来发现下一代有效的抗生素。这些抗生素还将为公众提供更强大的防御生物恐怖威胁的能力。

DESCRIPTION (provided by applicant): An increase in the incidence of infections caused by drug resistant pathogens coupled to the need to develop antibacterial countermeasures against bioterror agents has resulted in a critical need for the development of new dual-use antibiotics. The goal of this project is to develop novel, broad-spectrum antibiotics active against bacteria of concern from a biodefense standpoint including Yersinia pestis and Bacillus anthracis as well as clinically important multi-drug-resistant bacterial pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), Acinetobacter baumannii, Enterobacteria expressing an extended-spectrum beta lactamases (ESBL) and Pseudomonas aeruginosa. This goal will be achieved by applying a new cultivation approach that utilizes a trap for the in situ capture of previously uncultured actinomycetes, the source of most antibiotics on the market today. These novel actinomycetes will then be explored for their ability to produce new antibiotics. Here we present data that demonstrates the ability of our in situ trap to: 1) efficiently enrich for actinomycetes, 2) select for different actinomycetes Genera than traditional microbiological methods and 3) isolate actinomycetes species that have not been previously discovered. In this Phase I project we will develop the trap method into a drug development pipeline and evaluate the success of this technology based on the uniqueness of the antimicrobial compounds identified from our trap-derived actinomycetes. Specific aims of the project are: Aim1: To evaluate the novelty of actinomycetes isolated by the NovoBiotic trap method, we will isolate 1000 novel actinomycetes using the trap technology and identify these species. Aim 2: To elicit antibiotic production from our 1000 trap-derived actinomycetes and prioritize 50 isolates for analytical chemistry analyses. Aim 3: To dereplicate the antibacterial compounds produced by our trap-derived Actinomycetes. The results of Phase I will be used in Phase II to develop the large-scale cultivation, fermentation, chemical dereplication of trap-derived actinomycetes necessary for the development of dual-use antibiotics. PUBLIC HEALTH RELEVANCE: Bacteria that cause infections in the community and in hospitals are becoming increasingly resistant to currently available antibiotics, so there is an urgent need for new antibiotics that will ensure public health in the years to come. The purpose of this project is to employ a new technology to discover the next generation of effective antibiotics. These antibiotics will also provide the public with a stronger defense against the threat of bioterror.