Exploiting deep ocean biology for biomedical discovery

描述（由申请人提供）：本领域申请寻求在罗德岛大学的三位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。此次合作将利用综合海洋钻探计划（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来支持IODP探险，从遥远的深海环境中分离新型微生物，用于药物发现。这些研究的最初重点将放在从南太平洋环流中提取的沉积物岩心中培养的各种细菌上，这是一个巨大的海洋中部区域，尚未被药物发现调查所利用。AIM 1将从深海（约2000米）深处获得的海洋沉积物中分离出一种新的遗传多样性细菌。这些微生物将被分离出来，使用的方法是为适应低营养和高压环境的生命量身定制的。然后，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培养上清的半纯化部分进行。该试验（AIM 3）的重点将是ATCC和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。纯分子将定量测试细菌生长抑制和减少生物膜形成使用成熟的和尖端的方法。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是否能防止导管中形成生物膜，这是医院感染的一个有问题的来源。所有化合物都将进行额外的细胞毒性测试，并将足够数量的化合物提交给NIH分子文库小分子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，并将促进与药物发现相关科学的本科生和研究生的跨学科培训。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型抗菌剂。由于致病菌耐药菌株的出现，我们治疗传染病的能力日益受到损害。例如，重症监护病房中60%以上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。抗生素药物的发现跟不上日益增长的耐药性。这个项目将扩大我们对新抗生素的研究，包括来自最遥远的深海环境的微生物产生的新分子，这是一个非常有前途但大多未知的资源。

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.