Chemistry Core

项目摘要 微生物，尤指细菌，产生生物活性分子的能力，这些分子可以构成 治疗药物对抗重要的人类病原体形成了这一CETR应用的总体前提。 微生物生产者将是来自各种生态位的共生细菌。这些化验将导致 潜在治疗药物的发现将集中在耐多药的革兰氏阴性细菌和系统性 真菌病原体。化学核心将负责将生物中发现的活动转化为 对纯化的活性分子进行鉴定，这些分子具有足够的已知结构，具有二级功能 可以处理分析、结构-活性研究和靶标识别。这一总体目标将是 完成四项任务，提案后面的一节将更详细地介绍这些任务。 任务1：生产共生微生物代谢物组分，用于去复制和体外有效性和安全性 测试。 任务2：规模化生产有希望的组份，用于体内测试和结构鉴定。 任务3：纯化活性分子并对其结构进行表征/S 任务4：先进体内PK/PD的规模化生产及其作用机制的测定。

Project Summary The ability of microbes, especially bacteria, to produce biologically active molecules that can form the basis of therapeutic agents to confront important human pathogens forms the overall premise of this CETR application. The microbial producers will be symbiotic bacteria from a variety of niches. The assays that will lead to the discovery of potential therapeutic agents will focus on multidrug resistant Gram-negative bacteria and systemic fungal pathogens. The Chemistry Core will be responsible for converting the activity discovered in biological assays into purified active molecules with known structures in sufficient amounts that secondary functional assays, structure-activity studies, and target identification can be addressed. This overall goal will be accomplished with four tasks, which are described in much greater detail in a later section of the proposal. Task 1: Produce symbiotic microbe metabolite fractions for dereplication and in vitro efficacy and safety testing. Task 2: Scale-production of promising fraction for in vivo testing and structural elucidation. Task 3: Purify and structurally characterize the active molecule/s. Task 4: Large-scale production for advanced in vivo PK/PD and mechanism of action determination.