Novel Antibiotics from Marine Invertebrate Microbes

来自海洋无脊椎动物微生物的新型抗生素

• 批准号: 9407904
• 负责人: Amy Lynn Spoering
• 金额: $ 28.62万
• 依托单位: NOVOBIOTIC PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-09 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9407904
• 关键词: Address; Agar; Animal Sources; Animals; Anti-Bacterial Agents; Antibiotics; Antimicrobial Resistance; Back; Bacteria; Biological; Biological Assay; Cells; Chemicals; Collaborations; Collection; Complex; Development; Devices; Diffuse; Diffusion; Environment; Escherichia coli; Fractionation; Funding; Future; Genes; Goals; Growth; Growth Factor; In Situ; Incubated; Invertebrates; Laboratories; Marine Invertebrates; Marines; Mass Spectrum Analysis; Membrane; Methicillin Resistance; Methodology; Methods; Microbe; New England; Nutrient; Organism; Phase; Phylogenetic Analysis; Porifera; Property; Public Health; Recombinant DNA; Research; Resistance; Resolution; Resources; Soil; Source; Staphylococcus aureus; Sterility; Surface; Techniques; Technology; Testing; Therapeutic; Toxic effect; United States National Institutes of Health; Vancomycin resistant enterococcus; Variant; Work; antimicrobial; aquarium; base; cell growth; combat; coral; cytotoxicity; design; flexibility; innovation; microbial; microorganism; multi-drug resistant pathogen; novel; pathogen; prevent; screening; success

ABSTRACT The rise of multi-drug resistant pathogens, particularly ESKAPE pathogens, is a major public health concern. One effective countermeasure against such pathogens is novel antibiotics, but the rate of antibiotic discovery has been in steady decline. One particularly promising source of novel antibiotics is microbial species because most of them have never been cultivated or explored. This is especially true about marine species, specifically microbes living in association with invertebrates: such symbioses are known producers of bioactive compounds, these compounds likely originate from associated microbes, but only few of them are available in culture. We have designed and developed several proprietary technology platforms to grow and isolate such “uncultivable” microorganisms. These platforms are based on a simple idea: strains that do not grow in the lab can be grown in their natural environments if placed into small diffusion chambers. Cells inside such chambers, if returned back to the original environment, will be naturally fed by nutrients and growth factors diffusing through semipermeable membranes. This approach has resulted in the discovery of several new compounds, including teixobactin, an exciting new class of antibiotic that is active against resistant pathogens. This general approach can be used to grow invertebrate-associated, previously uncultivated microorganisms as well. For this project, we designed diffusion chambers that are flexible and can assume the topography of the animal, thus providing an immediate contact with the host – and the compounds it produces. In preliminary studies, we validated this general approach by growing a diverse collection of novel microorganisms showing antimicrobial activities. Here we will capitalize on these advances and achieve the following Specific Aims. Aim 1. Developing a method to grow and isolate novel microbial species living in association with marine invertebrates. We will use our new method to isolate 5000 microorganisms from 4 invertebrate species. Aim 2. Screening for antimicrobial activity. We will ferment the strains from Aim 1 and screen them against a panel of Gram-negative and Gram-positive pathogens, prioritizing 100 strains for chemical dereplication. Aim 3. Chemical dereplication of antimicrobial compounds. Using traditional separation methodologies, bioassay-guided fractionation, and high-resolution mass spectrometry, we will identify extracts with novel antimicrobial compounds and isolate these compounds into pure substances. We aim at discovering 1-3 novel compounds with low toxicity and a good spectrum of activity and potency. The end products of this project, an innovative cultivation platform, a large collection of novel marine microorganisms, and a selection of antimicrobials they produce, will set the stage for development of novel antibiotics in the future Phase II application.

摘要 多药耐药病原体，特别是ESKAPE病原体的增加是一个重大的公共卫生问题， 关心针对这些病原体的一种有效对策是新型抗生素，但抗生素的使用率 发现一直在稳步下降。一个特别有希望的新型抗生素来源是微生物物种 因为它们中的大多数从未被开发或开发过。海洋物种尤其如此， 特别是与无脊椎动物生活在一起的微生物：这种共生体是已知的生物活性物质的生产者。 化合物，这些化合物可能来源于相关的微生物，但其中只有少数是可利用的， 文化我们设计和开发了多个专有技术平台来增长和隔离此类产品 “不可培养的”微生物。 这些平台基于一个简单的想法：不能在实验室中生长的菌株可以在其 自然环境中，如果放入小扩散室。如果将这些小室中的细胞放回 原始环境，将自然喂养的营养物质和生长因子扩散通过半渗透 膜。这种方法导致了几种新化合物的发现，包括teixobactin， 令人兴奋的新型抗生素，对耐药病原体有效。这种通用方法可用于 生长无脊椎动物相关的，以前未培养的微生物以及。在这个项目中，我们设计了 扩散室是柔性的，并且可以呈现动物的形貌，从而提供即时的 与宿主的接触以及它产生的化合物在初步研究中，我们验证了这种一般方法 通过培养具有抗微生物活性的新型微生物的多样性集合。在这里，我们将利用 这些进步，并实现以下具体目标。 目标1.开发一种培养和分离与海洋生物相关的新微生物物种的方法 无脊椎动物我们将使用我们的新方法从4种无脊椎动物中分离出5000种微生物。 目标2.筛选抗菌活性。我们将发酵目标1的菌株， 一组革兰氏阴性和革兰氏阳性病原体，优先选择100种菌株进行化学去复制。 目标3.抗菌化合物的化学去复制。使用传统的分离方法， 生物测定指导的分馏，和高分辨率质谱，我们将确定提取物与新的 抗微生物化合物并将这些化合物分离成纯物质。我们的目标是发现1-3部小说 具有低毒性和良好的活性和效力谱的化合物。 该项目的最终产品，一个创新的培育平台，大量收集新颖的海洋生物， 微生物，以及它们产生的抗菌剂的选择，将为开发新的抗菌剂奠定基础。 抗生素在未来的第二阶段应用。