Exploiting deep ocean biology for biomedical discovery

描述(由申请人提供)：这一领域的申请寻求在罗德岛大学的三名研究人员之间建立一种新的合作，在海洋微生物天然产品化学、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)的探险，提供进入世界大洋海底的通道。我们的提案寻求通过从偏远的深海环境中分离出新的微生物来进行药物发现，从而利用支持IODP探险的数百万美元的联邦资金。这些研究的最初重点将是从南太平洋环流内取回的沉积物岩芯中培养出的各种细菌。南太平洋环流是一个巨大的中洋区域，药物发现调查尚未进入该区域。AIM 1将创建一个从深海(&gt；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生命定制方法进行分离。天然产物化学(AIM 2)将把这些生物的生物合成能力与其次生代谢物的药理学评估联系起来。抗生素测试将对纯微生物代谢物和来自培养上清液的半纯化部分进行。这项测试的重点(目标3)将是ATCC和临床多重耐药金黄色葡萄球菌、鲍曼不动杆菌、大肠杆菌、铜绿假单胞菌和肺炎克雷伯菌的生长抑制。因此，该项目将专注于寻找针对最有问题的临床病原体的抗生素。纯分子将使用成熟和尖端的方法对细菌生长抑制和生物膜形成的减少进行定量测试。例如，防止生物膜形成的化合物将在血管内导管模型中进行测试。这些测试将确定抗生素能否防止导尿管中生物膜的形成，导尿管是医院感染的一个问题来源。所有化合物都将接受额外的细胞毒性测试，足够数量的化合物将被提交给NIH分子图书馆小分子储存库进行更全面的生物医学评估。拟议的合作将提高罗德岛大学健康相关研究的竞争力，并将促进本科生和研究生在药物发现相关科学方面的跨学科培训。与人类健康的相关性：该项目的长期目标是发现新的抗菌剂，用于治疗耐药细菌感染。我们治疗传染病的能力正越来越多地受到抗药性病原菌株的出现的影响。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搜索，将来自最偏远深海环境的微生物产生的新分子包括在内，这是一种非常有希望但大多未知的资源。 公共卫生相关性：该项目将调查以前无法获取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。

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.