High throughput antibiotic discovery from the uncultivated microbial majority.

描述（由申请人提供）：该项目的长期目标是开发针对生物战剂和常见耐药病原体的新型广谱抗生素。基因工程、多重耐药菌株作为生物恐怖主义的潜在用途，以及目前传统耐药病原体的传播，都需要开发新型抗生素。目前使用的大多数抗生素是从不到1%的微生物物种中获得的，因为目前的方法无法培养绝大多数物种。剩下的99%的物种基本上代表了无限的微生物多样性，以发现新的抗生素。在这个一期项目中，我们的目标是开发一种工业规模的方法来培养和筛选以前未培养的细菌，包括放线菌，并从这种未开发的次生代谢物来源中获得生产新型广谱抗生素的原理证明。为了获得“不可培养”的物种，我们将利用我们的专利方法，基于环境微生物的原位培养，然后在体外驯化。为了实现这一目标，我们将把该方法发展成为一个独特的高通量技术平台，用于大规模培养和鉴定来自“不可培养”微生物的新抗生素。该项目的具体目标是：目标1：开发芯片，这是一种结合数百个微型扩散室的培养装置，作为一种快速、高通量、原位培养和驯化“不可培养”微生物的技术；目标2：使用一组多重耐药病原体和生物战制剂确定具有广谱抗菌活性的物种；目的3：研究新发现活性物质的化学新颖性。最终产品将是发现新型抗菌剂的管道，我们将在第二阶段充分利用它来开发新的广谱化合物。抗微生物药物的年市场规模为250亿美元，一些广谱药物的销售额超过10亿美元。II期的大规模筛选将产生多种候选分子，这些分子将经过详细的验证，最终产生针对该市场的新抗生素产品。

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop novel, broad-spectrum antibiotics against both biowarfare agents and common drug resistant pathogens. The potential use of engineered, multi-drug-resistant strains as agents of bioterrorism, and the current spread of conventional drug resistant pathogens necessitate the development of novel antibiotics. Most antibiotics in use today have been obtained from less than 1% of microbial species due to the inability to culture the vast majority of species by current methods. The remaining 99% of species represent essentially an unlimited diversity of microorganisms to discover novel antibiotics. In this Phase I project we aim to develop an industrial-scale methodology to grow and screen previously uncultivated bacteria, including Actinobacteria, and obtain proof-of-principle for production of novel broad-spectrum antibiotics from this untapped source of secondary metabolites. To access the "uncultivable" species, we will capitalize on our proprietary method based on in situ cultivation of environmental microorganisms, followed by their domestication in vitro. To achieve this goal, we will develop the method into a unique high throughput technology platform for massive cultivation and identification of new antibiotics from "uncultivable" microorganisms. The specific aims of the project are: Aim 1: Develop ichip, the cultivation device combining hundreds of miniature diffusion chambers as a technology for a rapid, high throughput, in situ cultivation and domestication of "uncultivable" microorganisms; Aim 2: Identify species with broad spectrum antimicrobial activities using a panel of multidrug resistant pathogens and biowarfare agents; Aim 3: Investigate the chemical novelty of the discovered activities. The end product will be a pipeline for discovery of novel antimicrobials, which we will fully utilize in Phase II to develop novel broad spectrum compounds. The annual market for antimicrobials is $25 billion, and several broad-spectrum drugs have sales in excess of $1 billion. The large-scale screening in Phase II will produce a variety of candidate molecules, which will undergo detailed validation, ultimately resulting in new antibiotic products targeting this market. PUBLIC HEALTH RELEVANCE: The rapid acquisition of resistance of bacterial pathogens in both community and hospital based infections coupled with the decreased investment in novel antibiotic development by large pharmaceutical companies represents an impending public health crisis. The purpose of this project is to develop a new technology to discover novel antibiotics. These new antibiotics will provide the public with a stronger defense whether the threat is from conventional or bioterror bacterial pathogens.