High throughput antibiotic discovery from the uncultivated microbial majority.

从大多数未培养的微生物中发现高通量抗生素。

• 批准号: 8039188
• 负责人: Amy Lynn Spoering
• 金额: $ 29.99万
• 依托单位: NOVOBIOTIC PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-08 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8039188
• 关键词: Acinetobacter baumannii; Actinobacteria class; Anti-Bacterial Agents; Antibiotics; Bacillus anthracis; Bacteria; Biological; Biological Assay; Biological Warfare; Biomass; Bioterrorism; Cells; Chemicals; Collection; Community Hospitals; Complex; Coupled; Data; Development; Devices; Diffusion; Drug resistance; Engineering; Enterobacteriaceae; Environment; Escherichia coli; Exhibits; Fermentation; Fractionation; Frequencies; Goals; Gram-Positive Bacteria; Growth; In Situ; In Vitro; Incubated; Infection; Investments; Mammalian Cell; Marketing; Mass Spectrum Analysis; Methodology; Methods; Multi-Drug Resistance; One-Step dentin bonding system; Organism; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phylogenetic Analysis; Procedures; Production; Pseudomonas aeruginosa; Public Health; Resolution; Resources; Rest; Sales; Screening procedure; Small Business Innovation Research Grant; Solutions; Source; Staging; Staphylococcus aureus; Technology; Testing; Time; Validation; Vancomycin resistant enterococcus; Variant; Yersinia pestis; antimicrobial; bacterial resistance; base; beta-Lactamase; cell growth; cytotoxicity; design; high throughput technology; methicillin resistant Staphylococcus aureus; microbial; microorganism; miniaturize; new technology; novel; pathogen; preference; public health relevance; rRNA Genes; resistant strain; success

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.

描述（由申请人提供）：该项目的长期目标是开发针对生物乳化剂和常见耐药病原体的新型，广谱抗生素。工程，多药抗性菌株作为生物恐怖主义的潜在用途以及常规耐药病原体的当前传播需要开发新型抗生素。由于无法通过当前方法培养绝大多数物种，因此当今使用的大多数抗生素是从不到1％的微生物物种中获得的。其余99％的物种本质上代表了微生物的无限多样性，以发现新型抗生素。在这个阶段I项目中，我们旨在开发一种工业规模的方法，以种植和筛选先前未经培养的细菌，包括静脉细菌，并从这种未开发的次生代谢物来源中获得新型广谱抗生素的原则证明。为了获得“不可养殖”的物种，我们将基于原位种植环境微生物的原位利用我们的专有方法，然后在体外进行驯化。为了实现这一目标，我们将将该方法开发为一个独特的高吞吐技术平台，以大规模培养和从“无法养活”的微生物中鉴定新的抗生素。该项目的具体目的是：目标1：开发ICHIP，将数百个微型扩散室与快速，高通量，现场种植和“无法养活”的微生物的驯化相结合的技术； AIM 2：使用一组耐多药病原体和生物质量剂鉴定具有广谱抗菌活性的物种；目标3：研究发现活动的化学新颖性。最终产品将是发现新型抗菌剂的管道，我们将在II期中充分利用它来开发新型的广谱化合物。抗菌剂的年度市场为250亿美元，几种广谱药物的销售额超过10亿美元。第二阶段的大规模筛查将产生各种候选分子，这些分子将经过详细的验证，最终导致针对该市场的新抗生素产品。 公共卫生相关性：在社区和基于医院的感染中迅速获得细菌病原体的抗性，加上大型制药公司对新型抗生素开发的投资减少，这是一场即将发生的公共卫生危机。该项目的目的是开发一种新技术来发现新型抗生素。这些新的抗生素将为公众提供更强大的辩护，无论威胁是传统的还是生物疗法的细菌病原体。