Isolating novel actinomycetes for antibiotic discovery

分离新型放线菌以发现抗生素

• 批准号: 7480833
• 负责人: Losee Lucy Ling
• 金额: $ 29.9万
• 依托单位: NOVOBIOTIC PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7480833
• 关键词: Acinetobacter baumannii; Actinobacteria class; Actinomyces; Agar; Analytical Chemistry; Anti-Bacterial Agents; Antibiotics; Bacillus anthracis; Bacteria; Binding; Biological Assay; Biological Factors; Cells; Chemicals; Communities; Coupled; Data; Databases; Development; Drug resistance; Ensure; Enterobacteriaceae; Fermentation; Fractionation; Gel; Genbank; Goals; Growth; Hospitals; Hyphae; In Situ; Incidence; Incubated; Infection; Laboratories; Lead; Mammalian Cell; Marketing; Mass Spectrum Analysis; Membrane; Methodology; Methods; Mining; Multi-Drug Resistance; Nutrient; Penetration; Phase; Process; Production; Pseudomonas aeruginosa; Public Health; Purpose; Recombinant DNA; Resistance; Resolution; Resources; Ribosomal DNA; Screening procedure; Sequence Analysis; Serum; Signaling Molecule; Soil; Solid; Source; Standards of Weights and Measures; Sterility; Surface; Technology; Today; Toxic effect; Vancomycin resistant enterococcus; Work; Yersinia pestis; antimicrobial; base; beta-Lactamase; biodefense; cytotoxicity; detector; drug development; drug discovery; gellan gum; methicillin resistant Staphylococcus aureus; microorganism; molecular mass; new technology; next generation; novel; pathogen; scale up; soil sampling; success

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.

描述（由申请人提供）：由耐药病原体引起的感染发生率的增加，加上开发针对生物恐怖剂的抗菌对策的需要，导致迫切需要开发新的双重用途抗生素。该项目的目标是开发新型广谱抗生素，从生物防御的角度有效对抗相关细菌，包括鼠疫耶尔森菌和炭疽杆菌，以及临床上重要的多重耐药细菌病原体，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。然后将探索这些新型放线菌生产新抗生素的能力。在这里，我们提供的数据证明了我们的原位捕获的能力：1）有效富集放线菌，2）选择比传统微生物方法不同的放线菌属，3）分离以前未发现的放线菌物种。在这个第一阶段项目中，我们将把陷阱方法开发成药物开发管道，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该技术的成功。该项目的具体目标是： 目标1：为了评估NovoBiotic诱捕法分离的放线菌的新颖性，我们将利用诱捕技术分离1000种新型放线菌并鉴定这些物种。目标 2：从我们的 1000 种诱捕放线菌中诱导产生抗生素，并优先对 50 种分离株进行分析化学分析。目标 3：消除由我们的诱捕放线菌产生的抗菌化合物。第一阶段的成果将用于第二阶段，以开发两用抗生素开发所需的陷阱源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来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有力的防御措施，抵御生物恐怖的威胁。