Developing Novel Antibiotics Against Yersinia pestis

开发针对鼠疫耶尔森氏菌的新型抗生素

• 批准号: 7108156
• 负责人: Losee Lucy Ling
• 金额: $ 179.57万
• 依托单位: NOVOBIOTIC PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7108156
• 关键词: Yersinia pestis; Yersinia pestis disease; antibiotics; antiinfective agents; bioterrorism /chemical warfare; chemical synthesis; drug design /synthesis /production; drug discovery /isolation; mass spectrometry; microorganism disease chemotherapy; nuclear magnetic resonance spectroscopy; polymerase chain reaction; therapy design /development

DESCRIPTION (provided by applicant): The overall goal of this project is to develop broad-spectrum antibiotics against Yersinia pestis and other important human pathogens. The potential use of engineered, multi-drug-resistant strains as agents of bioterrorism necessitates the development of new anti-Y. pestis therapies. This is a challenging goal, since the last novel class of broad-spectrum antibiotics was introduced over 20 years ago. NovoBiotic has a proprietary technology capable of meeting this challenge. We will obtain new antimicrobials from a previously inaccessible source - unculturable microorganisms that make up 99% of the total microbial diversity. In Phase I, our goal was to develop an industrial-scale technology to grow and screen previously unculturable microorganisms for antimicrobial production. The main milestone was to "domesticate" unculturable organisms to enable scale-up under conventional growth conditions; and developing a screen capable of detecting antimicrobial activity at a rate of equal to or >10(exp5) isolates/year. We achieved these milestones ahead of schedule, and have in place a robust technology that will enable us to discover new antibiotics in this Phase II project. Our preliminary results indicate that unculturable microorganisms produce novel, broad- spectrum antimicrobial compounds. The anti-infectives we develop will target a global $24 billion market. Broad-spectrum antibiotics are the top earners, with several drugs having sales in excess of $1 billion. Phase II Specific Aims are: 1. Large-scale isolation of lead antimicrobial compounds from unculturable bacteria. Milestone: obtain 200 purified, potentially novel lead compounds. 2. In vitro validation and structure of lead compounds. a. Structure determination. All compounds derived from the bioassay guided fractionation will have their structures elucidated. We will define the basic molecular architecture using advanced MS and NMR. b. Biological validation. We will determine the following properties of the purified early leads: potency (MIC) against a panel of test organisms; MBC; activity in the presence of serum; toxicity against animal cells; resistance development; specificity of action. Milestone: obtain 50 leads with novel structure. 3. In vivo validation. The lead compounds that pass preliminary validation will be subjected to a detailed evaluation in an animal model. Milestone: obtain 3-5 advanced validated leads for drug development. Relevance to human health: There is an acute need for new antibiotics to combat conventional and biowarfare drug-resistant pathogens. The compounds we discover in this project will lead to new, broad- spectrum antibiotics.

描述（由申请人提供）：该项目的总体目标是开发针对耶尔森氏菌和其他重要人类病原体的广谱抗生素。工程，多药抗性的菌株的潜在使用是生物恐怖主义的药物，因此需要开发新的抗Y。瘟疫疗法。这是一个具有挑战性的目标，因为在20年前引入了最后一类小型广谱抗生素类。 Novobiotic具有一项能够应对这一挑战的专有技术。我们将从以前难以访问的来源获得新的抗菌剂 - 占总微生物多样性的99％的不可养生的微生物。在第一阶段，我们的目标是开发一种工业规模的技术，以生长和筛选以前无法培养的微生物来抗菌生产。主要的里程碑是“驯化”不可养殖的生物，以在常规生长条件下进行扩大。并开发一个能够以等于或> 10（EXP5）/年的速率检测抗菌活性的屏幕。我们提前达到了这些里程碑，并拥有一项强大的技术，该技术将使我们能够在此II阶段项目中发现新的抗生素。我们的初步结果表明，不可培养的微生物产生了新型的广谱抗菌化合物。我们开发的反感染者将针对全球240亿美元的市场。广谱抗生素是最高收入者，其中几种销售额超过10亿美元。第二阶段的特定目的是：1。从不可培养细菌中大规模分离铅抗菌化合物。里程碑：获得200种纯化的，潜在的新型铅化合物。 2。铅化合物的体外验证和结构。一个。结构确定。从生物测定的指导分馏中得出的所有化合物都将阐明其结构。我们将使用高级MS和NMR定义基本分子体系结构。 b。生物验证。我们将确定纯化的早期铅的以下特性：针对一组测试生物的效力（MIC）； MBC;血清存在的活性；对动物细胞的毒性；抵抗发展；作用的特异性。里程碑：获得具有新结构的50条线索。 3。体内验证。通过初步验证的铅化合物将在动物模型中进行详细评估。里程碑：获得3-5个经过高级验证的药物开发潜在客户。与人类健康的相关性：急需新的抗生素来对抗常规和抗药性药物的病原体。我们在该项目中发现的化合物将导致新的，广泛的抗生素。