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氏菌的疗法，鼠疫耶尔森氏菌是鼠疫的病原体，也是最危险的潜在生物武器之一。我们最近开发了一种生长以前“不可培养的”微生物的通用方法（Kaeberlein，T.，刘易斯，K.，和Epstein，S. S.（2002年）的报告。Science 296：1127-1129），并且这种专有技术将作为抗生素发现的平台。目前使用的大多数抗生素都来自可培养的微生物，占所有物种的不到1%。新化合物的发现在70年代由于可栽培物种的过度开采而基本停止。不可培养的微生物是这个星球上生物多样性最丰富的来源，我们将利用这一基本上无限的资源来发现对抗Y。鼠疫第一阶段的目标是从不可培养的微生物中筛选抗菌化合物，并通过鉴定具有化学新奇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，最终产生新的抗生素产品。 具体目标是： 1.获取和筛选不可培养微生物的工具。扩散室方法将用于分离和培养不可培养的微生物。（里程碑：我们将通过该方法获得1，000个新分离株）。将开发用于快速分离、筛选和扩大规模的其他新方法：将鉴定使不可培养的微生物在体外合成培养基上生长的辅助生物。驯化不可培养的微生物将导致在常规合成培养基上生长的变体。（里程碑：使用这些方法，我们将实现>105分离株/年的抗生素生产者筛选率）。 2.提取物筛选和初步验证。（里程碑：筛选4，000份浸提液）。 3.去复制和结构确定。（里程碑：确定5种化学新化合物）。

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).