Developing Novel Antibiotics Against Yersinia pestis

描述（由研究者提供）：该项目的总体目标是开发针对鼠疫耶尔森菌的治疗方法，鼠疫是鼠疫的病原体，也是最危险的潜在生物武器之一。我们最近开发了一种培养以前“不可培养”微生物的一般方法（Kaeberlein， T., Lewis， K., and Epstein， S.S.(2002)）。科学296:1127-1129)，这项专利技术将作为发现抗生素的平台。目前使用的大多数抗生素来自可培养的微生物，占所有物种的不到1%。由于对可栽培物种的过度开采，新化合物的发现在70年代基本上停止了。不可培养的微生物是这个星球上最丰富的生物多样性来源，我们将利用这一基本上无限的资源来发现对抗鼠疫杆菌的抗生素。第一阶段的目标是从不可培养的微生物中建立抗菌化合物的筛选，并通过鉴定具有化学新颖性的化合物来获得该技术的原理证明。这将使第二阶段的大规模筛选和验证成为可能，这将产生先导化合物，最终产生一种新的抗生素产品。

DESCRIPTION (provided by investigator): The overall goal of this project is to develop therapies against Yersinia pestis, the causative agent of plague and one of the most dangerous potential bioweapons. We recently developed a general method to grow previously "unculturable" microorganisms (Kaeberlein, T., Lewis, K., and Epstein, S.S. (2002). Science 296:1127-1129), and this proprietary technology will serve as a platform for antibiotic discovery. Most antibiotics currently in use are derived from cultivable microorganisms that make up <1% of all species. Discovery of novel compounds essentially ceased in the 70s due to overmining of cultivable species. Unculturable microorganisms are the richest source of biodiversity on this planet, and we will access this essentially unlimited resource to discover antibiotics acting against Y. pestis. The goal of Phase I is to establish screens for antimicrobial compounds from unculturable microorganisms, and obtain proof-of principle for this technology by identifying compounds with chemical novelty. This will enable large-scale screening and validation in Phase II that will produce lead compounds, ultimately resulting in a new antibiotic product. The Specific Aims are: 1. Tools to obtain and screen unculturable microorganisms. The diffusion chamber approach will be used to isolate and grow unculturable microorganisms. (Milestone: we will obtain 1,000 novel isolates by this method). Additional novel methods for rapid isolation, screening and scale up will be developed: Helper organisms will be identified that enable growth of unculturable microorganisms on synthetic media in vitro. Domestication of unculturable microorganisms will result in variant growing on regular synthetic media. (Milestone: using these methods, we will achieve a rate of screening for antibiotic producers of >105 isolates/year). 2. Extract screening and preliminary validation. (Milestone: screen 4,000 extracts). 3. Dereplication and structure determination. (Milestone: identify 5 chemically novel compounds).