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

• 批准号: 8072185
• 负责人: Kerry Leigh McPhail
• 金额: $ 17.52万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8072185
• 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 Infections; 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; human migration; in vitro activity; in vivo; in vivo Model; infectious disease treatment; interest; microbial; microorganism; novel; novel therapeutics; pathogen; programs; public health relevance; research study; small molecule; solvent extraction; 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 Infections; 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; human migration; in vitro activity; in vivo; in vivo Model; infectious disease treatment; interest; microbial; microorganism; novel; novel therapeutics; pathogen; programs; public health relevance; research study; small molecule; solvent extraction

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新兴多药耐药性的全球阴影中，新抗生素的管道令人震惊。为了解决这种紧迫的公共卫生关注，必须不断寻求通过新机制起作用的新型结构新颖的分子。在过去的25年中，被批准为药物的所有新化学实体中有50％以自然产物铅化合物为基础。因此，来自多种多样的系统发育独特的生物是下一代治疗剂的关键导线。该提案的总体目的是使用微观化学和生物学技术来评估最近发现的深海通风生物作为具有前所未有的小分子天然产品的来源，具有与药物相关的抗感染性能，并将通过以下特定目的来实现：1）获得和化学提取现场式现场培养和化学提取物的实验性和化学实验性的实验室培养机。 2）通过液相色谱质 - 质谱法（LC-MS）和自动微流毛细血管核磁共振（NMR）光谱法化学介绍了通风库HPLC分数的库。 3）在生物学上介绍了通风孔样品文库的体外抗菌活性，并在细菌耐药性测定中测试纯化合物铅，并在快速，易于执行的斑马鱼感染模型中进行体内和体内。深层浸入式车辆收集的深层无脊椎动物和微生物垫将受到小规模提取，过滤和HPLC分馏，以组装HPLC分数的排气样品库。此外，经过相同方案的深通风细菌的实验室培养物将有助于样本文库。 HPLC分数文库将获得包括紫外线吸收，质谱和NMR光谱数据在内的分析数据，以快速鉴定已知或潜在的新型化合物。低重复的HPLC运行产生的其他数量的HPLC级分，将在微量滴定液体培养试验中测试针对临床相关的革兰氏阴性和革兰氏阴性细菌。在这些测定中具有活性的HPLC级分的纯化化合物将提交，以进一步评估多药耐药细菌病原体。此外，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测试抗菌纯化合物铅。 公共卫生相关性：抗生素传染病的治疗受到疾病中抗药性的迅速发展，导致微生物的抗药性，并需要不断发现新药物铅以新的方式产生其抗生素作用。这项研究的重点是评估不寻常的，最近发现的深海水热生物体，用于生产新型的天然产物以进行抗感染药物开发。天然产物是大多数认可的抗生素药物的来源，也是新型化合物类型的验证来源。