Microbial symbionts of marine invertebrates for antibiotic discovery

 描述(申请人提供)：这个项目的总体目标是发现新的抗生素来对抗重要的耐药病原体。针对这些病原体的有效对策之一是新型抗生素，但抗生素的发现率一直在稳步下降。所有新近引入的抗生素都是旧抗生素的衍生物，或者是几十年前发现的最初被丢弃的化合物的复兴所致，如达托霉素、利奈唑胺、协效剂和非达霉素类。临床使用的抗生素传统上是通过筛选易培养微生物的活性次生代谢物来发现的。这种资源占自然界所有微生物多样性的1%。另有99%的微生物未被开发，也是以前无法获得的，可以说是制造新型抗生素最有希望的单一资源。新生物公司通过使用独特的培养方法直接解决了抗生素发现的瓶颈：扩散箱和陷阱方法分离出以前无法培养的微生物。到目前为止，这种方法已经产生了25种新化合物，其速度远远高于预测的行业标准。其中几种化合物具有主要的新颖性，并且正在开发中，其中包括Novo10，一种DNA G-四链结合剂，目前正在与美国国家癌症研究所合作开发用于抗癌的药物；Novo22，一种细胞壁生物合成的大内酰胺抑制剂；lassmycin，一种结核分枝杆菌基本ClpP1P2C1蛋白酶的抑制剂；以及teixobactin，一种新的细胞壁合成抑制剂。该项目采取了下一步，将该技术扩展到浅水海洋无脊椎动物-微生物共生，在当地社区无处不在，很容易获得。从迄今进行的有限探索中，已经从海洋共生体中发现了许多具有独特性质的生物活性化合物，包括抗肿瘤和抗微生物化合物。有强有力的证据表明，正是与宿主无脊椎动物生活在一起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微生物物种，并筛选这些菌株的抗菌活性。我们将比较从扩散室、陷阱和常规培养中分离出的菌株的活性化合物的多样性和新颖性。这一第一阶段项目的最终结果将是证明新技术的概念，以从一个探索不足的微生物多样性来源发现抗生素：以前来自海洋无脊椎动物-微生物共生体的“不可培养”的微生物物种。

 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.