Anti-infective Natural Products from Deep Sea Vent Organisms

来自深海喷口生物的抗感染天然产物

基本信息

批准号：
7991051
负责人：
Kerry Leigh McPhail
金额：
$ 21.38万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7991051
关键词：
Address Anabolism Anaerobic Bacteria Anti-Bacterial Agents Anti-Infective Agents Antibiotics Bacteria Biochemical Biodiversity Biological Biological Assay Biological Factors Bioterrorism Blood capillaries Chemicals Collaborations Collection Communicable Diseases Complex Data Development Disease Drug resistance Ecology Ecosystem Embryo Environment Evaluation Event Exhibits Filtration Fractionation Genetic Template Global Change Global Warming Goals Gram-Negative Bacteria HIV Habitats High Pressure Liquid Chromatography Human In Vitro Infection Invertebrates Island Laboratories Laboratory culture Lead Libraries Light Liquid substance Marines Mass Spectrum Analysis Metagenomics Microbe Mining Modeling Molecular Multi-Drug Resistance Mycobacterium marinum NMR Spectroscopy Nuclear Magnetic Resonance Oceans Oregon Organic solvent product Organism Pattern Pharmaceutical Preparations Pharmacologic Substance Physiological Plague Production Property Protocols documentation Public Health Research Resistance Running Sampling Sea Shadowing (Histology)Signal Transduction Site Source Staphylococcal Infections Staphylococcus aureus Structure Techniques Testing Therapeutic Agents Universities Vent Zebrafish absorption antimicrobial antimicrobial drug aqueous bacterial resistance bactericide base capillary chemical genetics chemical synthesis clinically relevant combinatorial cryogenics drug development drug discovery fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether human migration in vitro activity in vivo in vivo Model infectious disease treatment interest microbial microorganism mycobacterial novel novel therapeutics pathogen programs public health relevance research study small molecule solvent extraction

项目摘要

DESCRIPTION (provided by applicant): In the global shadow of emerging multi-drug resistance in many human pathogens, the pipeline of new antibiotics is alarmingly depleted. To address this pressing public health concern, new types of structurally novel molecules that act via new mechanisms must constantly be sought. In the last 25 years, over 50% of all new chemical entities approved as drugs were based on a natural product lead compound. Thus, chemically diverse natural products from diverse, phylogenetically unique organisms are critical leads for the next generation of therapeutic agents. The overarching goal of this proposal is to use microscale chemical and biological techniques to evaluate recently discovered deep-sea vent organisms as a source of unprecedented small molecule natural products with medicinally-relevant anti-infective properties, and will be achieved by the following specific aims: 1) To obtain and chemically extract field-collected and laboratory-cultured deep vent organisms. 2) To chemically profile a library of vent sample HPLC fractions by liquid chromatograph-mass spectrometry (LC-MS) and automated microflow capillary nuclear magnetic resonance (NMR) spectroscopy. 3) To biologically profile the vent sample library for antimicrobial activity in vitro and to test pure compound leads in vitro in bacterial resistance assays and in vivo in rapid, easily performed zebrafish infection models. Deep vent invertebrates and microbial mats collected by deep submergence vehicles will be subjected to small-scale extraction, filtration and HPLC fractionation to assemble a vent sample library of HPLC fractions. Additionally, laboratory cultures of deep vent bacteria subjected to the same protocols will contribute to the sample library. Analytical data including UV absorption, mass spectrometric and NMR spectroscopic data will be obtained for the HPLC fraction library to enable rapid identification of known or potentially new types of chemical compounds. Additional quantities of these HPLC fractions generated by low replicate HPLC runs will be tested in microtiter liquid culture assays against clinically relevant Gram-positive and Gram-negative bacteria. Purified compounds from HPLC fractions with activity in these assays will be submitted for further evaluation against multi-drug resistant bacterial pathogens. In addition, antibacterial pure compound leads will be tested in in vivo models of mycobacterial and staphylococcal infections of embryonic zebrafish. PUBLIC HEALTH RELEVANCE: The treatment of infectious diseases with antibiotics is plagued by the rapid and inevitable development of drug-resistance in the disease causing microorganisms, and requires the constant discovery of new drug leads that produce their antibiotic effect in new ways. This research focuses on the evaluation of unusual, recently discovered deep-sea hydrothermal vent organisms for their production of novel types of natural products for anti-infective drug development. Natural products are the source of the majority of approved antibiotic drugs, and are also a proven source of new types of chemical compounds.

描述（由申请人提供）：在许多人类病原体中出现的多重耐药性的全球阴影下，新抗生素的研发管线正在惊人地枯竭。为了解决这一紧迫的公共卫生问题，必须不断寻找通过新机制发挥作用的新型结构新颖的分子。在过去 25 年中，超过 50% 被批准作为药物的新化学实体都是基于天然产物先导化合物。因此，来自不同的、系统发育独特的生物体的化学多样化的天然产物是下一代治疗剂的关键线索。该提案的总体目标是利用微型化学和生物技术来评估最近发现的深海喷口生物，将其作为具有医学相关抗感染特性的前所未有的小分子天然产物的来源，并将通过以下具体目标来实现： 1) 获取并化学提取现场收集和实验室培养的深口生物。 2) 通过液相色谱-质谱 (LC-MS) 和自动微流毛细管核磁共振 (NMR) 光谱对排气样品 HPLC 级分库进行化学分析。 3) 对排气口样品库的体外抗菌活性进行生物学分析，并在体外细菌耐药性测定和体内快速、易于执行的斑马鱼感染模型中测试纯化合物先导化合物。由深潜器收集的深部喷口无脊椎动物和微生物垫将进行小规模提取、过滤和 HPLC 分级分离，以组装 HPLC 组分的喷口样品库。此外，接受相同方案的深口细菌实验室培养物也将有助于样本库。 HPLC 馏分库将获得包括紫外吸收、质谱和核磁共振光谱数据在内的分析数据，以便能够快速识别已知或潜在的新型化合物。由低重复 HPLC 运行产生的额外数量的 HPLC 级分将在微量滴定液体培养测定中针对临床相关的革兰氏阳性和革兰氏阴性细菌进行测试。从 HPLC 级分中纯化的化合物在这些测定中具有活性，将提交用于针对多重耐药细菌病原体的进一步评估。此外，抗菌纯化合物引线将在胚胎斑马鱼的分枝杆菌和葡萄球菌感染的体内模型中进行测试。公共卫生相关性：用抗生素治疗传染病受到致病微生物快速且不可避免地产生耐药性的困扰，并且需要不断发现新的药物先导物，以新的方式产生抗生素作用。这项研究的重点是评估最近发现的不寻常的深海热液喷口生物，以生产用于抗感染药物开发的新型天然产物。天然产物是大多数已批准抗生素药物的来源，也是新型化合物的经过验证的来源。