Exploiting deep ocean biology for biomedical discovery

利用深海生物学进行生物医学发现

• 批准号: 8036853
• 负责人: David C Rowley
• 金额: $ 41.83万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-15 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8036853
• 关键词: Acinetobacter baumannii; Actinobacteria class; Antibiotics; Attention; Bacteria; Bacterial Infections; Biodiversity; Biological; Biological Assay; Biological Factors; Biology; Catheters; Clinical; Collaborations; Collection; Communicable Diseases; Drug resistance; Drug-sensitive; Environment; Escherichia coli; Evaluation; Expeditions; Fractionation; Funding; Goals; Growth; Health; High Pressure Liquid Chromatography; Hospitals; Human; Infection; Intensive Care Units; Investigation; Investigational Drugs; Klebsiella pneumonia bacterium; Libraries; Life; Link; Location; Marines; Measures; Medical Device; Medicine; Metabolism; Methods; Microbe; Microbial Biofilms; Microbiology; Modeling; Molecular Bank; Multi-Drug Resistance; Natural Products Chemistry; Nutrient; Oceans; Organism; Process; Property; Pseudomonas aeruginosa; Research; Research Personnel; Resistance; Resources; Rhode Island; Science; Seawater; Source; Staphylococcus aureus; Structure; Techniques; Testing; Training; United States National Institutes of Health; Universities; Work; antimicrobial drug; biomedical resource; combat; cytotoxicity test; drug discovery; graduate student; meter; microbial; microorganism; next generation; novel; pathogen; pathogenic bacteria; preclinical evaluation; pressure; prevent; programs; repository; research study; resistant strain; small molecule; tandem mass spectrometry; two-dimensional

DESCRIPTION (provided by applicant): This AREA application seeks to establish a new collaboration among three investigators at the University of Rhode Island with complementary expertise in marine microbial natural products chemistry, deep ocean microbiology, and antibiotics research. This collaboration will capitalize upon expeditions of the Integrated Ocean Drilling Program (IODP) to provide access to the seafloor of the world ocean. Our proposal seeks to leverage the millions of dollars of federal funds that support IODP expeditions by isolating novel microorganisms from remote, deep ocean environments for drug discovery. The initial focus for these studies will be on diverse bacteria cultivated from sediment cores retrieved within the South Pacific Gyre, an enormous mid-ocean zone that has yet to be accessed by drug discovery investigations. AIM 1 will create a novel collection of genetically diverse bacteria isolated from ocean sediments acquired at abyssal (>2000 m) depths. The microbes will be isolated using methods tailored to life adapted to low nutrient and high-pressure environments. Natural products chemistry (AIM 2) will then link the biosynthetic capabilities of these organisms with pharmacological evaluation of their secondary metabolites. Antibiotic testing will be conducted on pure microbial metabolites and semi-purified fractions from culture supernatants. The focus of this testing (AIM 3) will be growth inhibition of both ATCC and clinical strains of multiple drug resistant Staphylococcus aureus, Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Thus, this project will focus on finding antibiotics against the most problematic clinical pathogens. Pure molecules will be quantitatively tested for bacterial growth inhibition and reduction of biofilm formation using proven and cutting edge methods. For example, compounds that prevent biofilm formation will be tested in an intravascular catheter model. These tests will determine if antibiotic agents can prevent biofilms from forming in catheters, a problematic source of infections in hospitals. All compounds will be additionally tested for cytotoxicity and sufficient quantities will be submitted to the NIH Molecular Libraries Small Molecule Repository for more comprehensive biomedical evaluation. The proposed collaboration will enhance the competitiveness of health-related research at the University of Rhode Island and will promote cross-disciplinary training of both undergraduate and graduate students in sciences related to drug discovery. Human Health Relevance: The long-term goal of the project is the discovery of new antimicrobial agents useful in the treatment of drug-resistant bacterial infections. Our ability to treat infectious disease is increasingly compromised by the emergence of drug-resistant strains of pathogenic bacteria. For example, more than 60% of staph infections in intensive care units are resistant to at least one medicine commonly used to treat these infections. Antibiotic drug discovery is not keeping pace with rising resistance. This project will extend our search for new antibiotics to include novel molecules produced by microbes from the most remote deep ocean environments, a highly promising but mostly unknown resource. PUBLIC HEALTH RELEVANCE: This project will investigate previously inaccessible microbial biodiversity in the deep ocean as novel resources for biomedical discovery. A specific project goal is the discovery of potent new antibiotics to combat drug resistant pathogens.

描述（由申请人提供）：该区域申请旨在在罗得岛大学的三名研究人员之间建立新的合作，他们在海洋微生物天然产物化学，深海微生物学和抗生素研究方面具有互补的专业知识。这项合作将利用综合大洋钻探计划（IODP）的考察，提供进入世界海洋海底的通道。我们的提案旨在利用数百万美元的联邦基金，通过从遥远的深海环境中分离新的微生物来支持IODP探险。这些研究的最初重点将是从南太平洋环流内的沉积物岩心中培养出的各种细菌，南太平洋环流是一个巨大的海洋中部区域，尚未通过药物发现调查进入。AIM 1将创建一个从深海（>2000米）深度获得的海洋沉积物中分离出的遗传多样性细菌的新集合。这些微生物将使用适应低营养和高压环境的方法进行分离。天然产物化学（AIM 2）将把这些生物的生物合成能力与其次级代谢产物的药理学评价联系起来。将对纯微生物代谢产物和培养物上清液的半纯化组分进行抗生素检测。本试验（AIM 3）的重点是多重耐药金黄色葡萄球菌、鲍曼不动杆菌、大肠埃希菌、铜绿假单胞菌和肺炎克雷伯菌的ATCC和临床菌株的生长抑制。因此，该项目将重点寻找针对最有问题的临床病原体的抗生素。将使用经验证的尖端方法定量测试纯分子的细菌生长抑制和生物膜形成的减少。例如，将在血管内导管模型中测试防止生物膜形成的化合物。这些测试将确定抗生素是否可以防止导管中形成生物膜，这是医院感染的一个问题来源。所有化合物将额外进行细胞毒性试验，并将足够数量的化合物提交给NIH分子库小分子储存库，以进行更全面的生物医学评价。拟议的合作将提高罗得岛大学与健康相关的研究的竞争力，并将促进对本科生和研究生进行与药物发现相关的跨学科培训。人类健康相关性：该项目的长期目标是发现可用于治疗耐药细菌感染的新抗菌剂。我们治疗传染病的能力越来越受到病原菌耐药性菌株出现的影响。例如，重症监护病房中超过60%的葡萄球菌感染对至少一种通常用于治疗这些感染的药物具有耐药性。抗生素药物的发现没有跟上耐药性上升的步伐。该项目将扩大我们对新抗生素的研究，包括由最偏远的深海环境中的微生物产生的新分子，这是一种非常有前途但大多数未知的资源。 公共卫生相关性：该项目将调查以前无法进入的深海微生物生物多样性，作为生物医学发现的新资源。一个具体的项目目标是发现有效的新抗生素来对抗耐药病原体。

项目成果

Enhancement of Antibiotic Activity against Multidrug-Resistant Bacteria by the Efflux Pump Inhibitor 3,4-Dibromopyrrole-2,5-dione Isolated from a Pseudoalteromonas sp.

• DOI: 10.1021/np500775e
• 发表时间: 2015-03-01
• 期刊: JOURNAL OF NATURAL PRODUCTS
• 影响因子: 5.1
• 作者: Whalen, Kristen E.;Poulson-Ellestad, Kelsey L.;Mincer, Tracy J.
• 通讯作者: Mincer, Tracy J.

Targeted search for actinomycetes from nearshore and deep-sea marine sediments.

• DOI: 10.1111/1574-6941.12082
• 发表时间: 2013-06
• 期刊: FEMS microbiology ecology
• 影响因子: 4.2
• 作者: Prieto-Davó A;Villarreal-Gómez LJ;Forschner-Dancause S;Bull AT;Stach JE;Smith DC;Rowley DC;Jensen PR
• 通讯作者: Jensen PR

Going deep for drug discovery: an ocean to bedside approach to explore sub-seafloor microbes for the next generation of antibiotics.

• 发表时间: 2012-09
• 期刊: Medicine and health, Rhode Island
• 作者: Stephanie R. Forschner-Dancause;K. LaPlante;David C. Smith;D. Rowley