Novel Approaches to Accessing Secondary Metabolites

获取次生代谢物的新方法

• 批准号: 7080410
• 负责人: Losee Lucy Ling
• 金额: $ 49.98万
• 依托单位: NOVOBIOTIC PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7080410
• 关键词: Actinomyces; Yersinia pestis; antibiotics; drug design /synthesis /production; method development; microorganism culture

DESCRIPTION (provided by applicant): The overall goal of this project is to develop novel therapeutic agents against Yersinia pestis, the causative agent of plague and one of the most dangerous potential bioweapons. In this exploratory project, we will develop novel approaches to obtain previously inaccessible secondary metabolites from actinomycetes. These organisms have traditionally served as the main source for antibiotics. Recent whole genome sequencing of two well-studied streptomycete species revealed potential additional modules for synthesis of antibiotics. This agrees well with previous data from the literature indicating that the majority of antibiotics are not expressed under in vitro growth conditions. It is reasonable to assume that antibiotics are expressed in a natural environment, where they provide a competitive advantage to the producing organism. Our overall approach is to emulate the natural environment to elicit production of antibiotics. We will develop two elicitation methods in this project. According to our preliminary data, there is a particular type of compounds that emulate a critical aspect of the environment and act as antibiotic elicitors. A detailed examination of the ability of these substances to elicit production of previously unknown antibiotics will be performed with a panel of known actinomycetes. Another method of antibiotic elicitation will be based on culturing microorganisms in their natural environment, soil, in a diffusion chamber that we have previously used to grow "unculturable" microorganisms (Kaeberlein, T., Lewis, K., and Epstein, S.S. (2002) Science 296:1127-1129). Finding new compounds with antimicrobial activity from known organisms using elicitation will constitute proof of principle for the proposed approach. The methods we develop will allow for large-scale screening and validation in Phase II which will lead to the development of a new anti-Y. pestis therapy.

描述(申请人提供)：该项目的总体目标是开发针对鼠疫耶尔森氏菌的新型治疗剂，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。在这个探索性项目中，我们将开发新的方法来从放线菌中获得以前无法获得的次生代谢物。这些微生物传统上是抗生素的主要来源。最近对两个研究良好的链霉菌物种的全基因组测序揭示了潜在的用于合成抗生素的额外模块。这与以前的文献数据很好地一致，该数据表明大多数抗生素在体外生长条件下不表达。我们有理由认为，抗生素是在自然环境中表达的，在那里它们为生产的有机体提供了竞争优势。我们的总体方法是模仿自然环境来诱导抗生素的生产。在这个项目中，我们将开发两种启发式方法。根据我们的初步数据，有一种特殊类型的化合物可以模拟环境的一个关键方面，并作为抗生素的诱导剂。对这些物质诱导产生以前未知的抗生素的能力的详细检查将与一组已知的放线菌一起进行。另一种抗生素诱导的方法将基于在微生物的自然环境，土壤，在扩散室内培养微生物，我们以前曾用它来培养“不可培养的”微生物(Kaeberlein，T.，Lewis，K.和Epstein，S.S.(2002)Science 296：1127-1129)。利用启发式从已知生物体中寻找具有抗微生物活性的新化合物将构成拟议方法的原则证明。我们开发的方法将允许在第二阶段进行大规模筛选和验证，这将导致开发一种新的抗Y抗体。鼠疫疗法。