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

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）：在许多人类病原体出现多重耐药性的全球阴影下，新抗生素的管道正在惊人地枯竭。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分子。在过去的25年里，超过50%的新化学实体被批准为药物，是基于天然产物的先导化合物。因此，来自不同的、遗传学上独特的生物体的化学上不同的天然产物是下一代治疗剂的关键先导。本提案的首要目标是利用微型化学和生物技术，评价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品的来源，并将通过以下具体目标实现：1）获取和化学提取实地收集和实验室培养的深海喷口生物。2)通过液相色谱-质谱（LC-MS）和自动微流毛细管核磁共振（NMR）光谱法对排气样品HPLC馏分库进行化学分析。3)在体外对排气样品库的抗微生物活性进行生物学分析，并在细菌耐药性测定中在体外和在快速、容易进行的斑马鱼感染模型中在体内测试纯化合物先导化合物。将对深潜潜水器收集的深海喷口无脊椎动物和微生物垫进行小规模提取、过滤和HPLC分馏，以汇集一个喷口HPLC馏分样品库。此外，实验室培养的深海喷口细菌也将按照同样的程序进行培养，以充实样本库。将获得HPLC馏分库的分析数据，包括UV吸收、质谱和NMR光谱数据，以快速鉴定已知或潜在的新型化合物。将在针对临床相关革兰氏阳性菌和革兰氏阴性菌的微量滴定液体培养试验中检测通过低重复HPLC运行生成的额外量的这些HPLC馏分。将提交在这些试验中具有活性的HPLC级分的纯化化合物，以进一步评价其对多重耐药细菌病原体的作用。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电极导线。 公共卫生相关性：用抗生素治疗感染性疾病受到致病微生物中快速且不可避免的耐药性发展的困扰，并且需要不断发现以新方式产生其抗生素作用的新药先导物。这项研究的重点是评价最近发现的不寻常的深海热液喷口生物，以确定它们能否生产新型天然产品，用于开发抗感染药物。天然产品是大多数批准的抗生素药物的来源，也是新型化合物的来源。

项目成果

Development of a quantitative assay amenable for high-throughput screening to target the type II secretion system for new treatments against plant-pathogenic bacteria.

开发适合高通量筛选的定量测定法，以针对 II 型分泌系统进行针对植物病原菌的新治疗。

• DOI: 10.1177/1087057113485426
• 发表时间: 2013
• 期刊: Journal of biomolecular screening
• 作者: Tran,Nini;Zielke,RyszardA;Vining,OliverB;Azevedo,MarkD;Armstrong,DonaldJ;Banowetz,GaryM;McPhail,KerryL;Sikora,AleksandraE
• 通讯作者: Sikora,AleksandraE

Streptomyces spiramenti sp. nov., isolated from a deep-sea microbial mat.

螺旋链霉菌 sp.

• DOI: 10.1007/s00203-022-03326-6
• 发表时间: 2022
• 期刊: Archives of microbiology
• 影响因子: 2.8
• 作者: Loughran,RachelM;Diefendorf,CaitlinM;Reill-VanSise,JassmineR;Mitchell,EdwardA;Vining,OliverB;Gallegos,DavidA;Miller,Gregory;Koyack,MarcJ;Oline,DavidK;Rivers,OrionS;Ushijima,Blake;Saw,JimmyH;Gaylor,MichaelO;McPhail,Ker
• 通讯作者: McPhail,Ker