Microbial symbionts of marine invertebrates for antibiotic discovery

用于抗生素发现的海洋无脊椎动物的微生物共生体

• 批准号: 8978558
• 负责人: Amy Lynn Spoering
• 金额: $ 22.44万
• 依托单位: NOVOBIOTIC PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8978558
• 关键词: Address; Agar; Anabolism; Animal Sources; Antibiotics; Antineoplastic Agents; Back; Bacteria; Bacterial Infections; Cell Wall; Cells; Chemicals; Collaborations; Communities; Daptomycin; Development; Devices; Diffuse; Diffusion; Drug resistance; Environment; Escherichia coli; Floor; G-Quartets; Goals; Growth; Growth Factor; In Situ; Incubated; Industry; Invertebrates; Life; Linezolid; Marine Invertebrates; Marines; Massachusetts; Membrane; Methodology; Methods; Microbe; Mycobacterium tuberculosis; National Cancer Institute; Nature; Organism; Peptide Hydrolases; Phase; Phylogenetic Analysis; Property; Resources; Sea; Series; Source; Staphylococcus aureus; Sterility; Symbiosis; Techniques; Technology; Testing; Therapeutic; Urochordata; Vancomycin resistant enterococcus; Variant; Water; antimicrobial; base; combat; coral; design; feeding; inhibitor/antagonist; invertebrate host; methicillin resistant Staphylococcus aureus; microbial; microorganism; new technology; novel; pathogen; public health relevance; rRNA Genes; screening; seal; success; tumor

 DESCRIPTION (provided by applicant): The overall goal of this project is to discover novel antibiotics to combat important drug-resistant pathogens. One effective countermeasure against such pathogens is novel antibiotics, but the rate of antibiotic discovery has been in steady decline. All the more recently introduced antibiotics are derivatives of older antibiotics or resulted from revival of initially discarded compounds which were discovered decades ago such as daptomycin, linezolid, synercid and fidaxomycin. Clinically used antibiotics have traditionally been discovered by screening for active secondary metabolites of readily culturable microorganisms. This resource represents <1% of all microbial diversity in nature. The other >99% unexplored, and previously unavailable, microorganisms are arguably the single most promising resource for novel antibiotics. NovoBiotic directly addresses the bottleneck of antibiotic discovery by using unique cultivation approaches: the diffusion chamber and trap methodologies to isolate previously "uncultivable" microorganisms. This approach has resulted in 25 new compounds so far, at a rate far higher than the predicted industry standard. Several of these compounds are of principal novelty and are in development including Novo10, a DNA G-quadruplex binder, currently in development as an anti-cancer agent in collaboration with the National Cancer Institute; Novo22, a macrolactam inhibitor of cell wall biosynthesis; lassomycin, an inhibitor of the essential ClpP1P2C1 protease of M. tuberculosis; and teixobactin, a novel cell wall synthesis inhibitor. This project takes the next step and extends the technology to shallow water marine invertebrate- microbe symbioses, ubiquitously present and easily accessible in local communities. From the limited exploration conducted to date, a number of bioactive compounds with unique properties have been discovered from marine symbioses, including anti-tumor and anti-microbial compounds. There is strong evidence that it is the associated microorganisms living in association with the host invertebrates that produce the bioactive compounds. We will develop our methods to isolate novel microbial species living in association with marine invertebrates and screen these strains for antimicrobial activity. We will compare the diversity and novelty of active compounds from strains isolated from the diffusion chamber, trap and conventional plating. The end result of this Phase I project will be proof of concept of new technologies to discover antibiotics from a poorly explored source of microbial diversity: formerly "uncultivable" microbial species from marine invertebrate-microbe symbioses.

 描述（由适用提供）：该项目的总体目标是发现新颖的抗生素来对抗重要的耐药病原体。对这种病原体的一种有效的对策是新型抗生素，但是抗生素发现的速率一直在稳步下降。最近引入的抗生素是旧抗生素的衍生物，或者是由于几十年前发现的最初丢弃的化合物的复兴而产生的，例如Daptomycin，linezolid，Synercid和Fidaxycomin。传统上，临床使用的抗生素是通过筛查易于培养的微生物的活跃次级代谢产物来发现的。该资源在本质上占所有微生物多样性的1％。另一个> 99％的意外且以前无法使用的微生物可以说是新型抗生素的最有希望的资源。 Novobirotic通过使用独特的培养方法直接解决了抗生素发现的瓶颈：扩散室和陷阱方法以隔离以前“不可培养”的微生物。到目前为止，这种方法已经产生了25种新化合物，速度远高于预测的行业标准。这些化合物中的几种是主要的新颖性，正在开发中，包括Novo10，Novo10，DNA G-四链体粘合剂，目前正在与国家癌症研究所合作作为抗癌剂开发； Novo22，一种细胞壁生物合成的大酰酰胺抑制剂；拉索霉素是结核分枝杆菌基本CLPP1P2C1蛋白的抑制剂；和Telexobactin，一种新型的细胞壁合成抑制剂。该项目采取下一步，并将技术扩展到浅水海洋无脊椎动物 - 微生物符号，在当地社区中可容易地存在且易于访问。从迄今为止进行的有限探索中，从海洋符号（包括抗肿瘤和抗微生物化合物）中发现了许多具有独特特性的生物活性化合物。有充分的证据表明，与宿主无脊椎动物相关的相关微生物产生了生物活性化合物。我们将开发我们的方法来分离与海洋无脊椎动物相关的新型微生物物种，并筛选这些菌株以进行抗菌活性。我们将比较从扩散室，陷阱和常规板上分离的菌株的活性化合物的多样性和新颖性。该阶段项目的最终结果将是新技术的概念证明，从探索的微生物多样性来源发现抗生素：以前是从海洋无脊椎动物微晶状体符号中“不可养活”的微生物物种。