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.

抽象的 多药耐药病原体的兴起，尤其是埃斯卡普病原体，是一种主要的公共卫生 忧虑。对这种病原体的一种有效的对策是新型抗生素，但抗生素速率 发现一直在稳步下降。新型抗生素的一种特别有望的来源是微生物物种 因为他们中的大多数从未被培养或探索。对于海洋物种，尤其如此 特别是与无脊椎动物相关的微生物：此类符号是已知的生物活性生产者 化合物，这些化合物可能起源于相关的微生物，但其中只有很少的化合物在 文化。我们设计并开发了几个专有技术平台，以发展和隔离 “无法养殖”的微生物。 这些平台基于一个简单的想法：在实验室中不生长的菌株可以在他们的 自然环境，如果放入小扩散室。这样的室内的牢房，如果返回到 原始环境将自然地由营养和生长因子通过半透 膜。这种方法导致发现了几种新化合物，包括telexobactin， 令人兴奋的新类抗生素，可积极抵抗抗性病原体。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。对于这个项目，我们设计了 柔性室的扩散室，可以假设动物的地形，从而立即提供 与宿主接触 - 及其产生的化合物。在初步研究中，我们验证了这种一般方法 通过种植潜水员的新型微生物，显示抗菌活性。在这里我们将资本化 在这些进步上，并实现以下特定目标。 目标1。开发一种与海洋相关的新型微生物物种的方法 无脊椎动物。我们将使用新方法将5000种微生物与4种无脊椎动物分离。 目标2。筛查抗菌活性。我们将从AIM 1发酵菌株，然后将其筛选 一组革兰氏阴性和革兰氏阳性病原体，优先考虑100个化学菌株的菌株。 AIM 3。抗菌化合物的化学消除。使用传统的分离方法， 生物测定引导的分级和高分辨率的质谱法，我们将识别出具有新颖的提取物 抗菌化合物并将这些化合物分离为纯物质。我们旨在发现1-3小说 具有低毒性和良好活性和效力的化合物。 该项目的最终产品，一个创新的耕种平台，大量的新型海军陆战队 微生物以及它们产生的多种抗菌素的选择，将为发展的发展树立阶段 未来II期应用中的抗生素。