In Vitro Core

体外核心

基本信息

批准号：
8836960
负责人：
Cameron Robert Currie
金额：
$ 81.04万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8836960
关键词：
Address Animal Model Biodiversity Biological Biological Assay Biological Factors Cause of Death Cells Chemicals Collaborations Communication Communities Dose Drug Formulations Drug Kinetics Drug Stability Drug resistance Erythrocytes Fermentation Focus Groups Fractionation Genomics Goals Gram-Negative Bacteria Hemolysis Human In Vitro Laboratories Lead Mediating Mediation Microbe Mus Natural Product Drug Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacy Schools Poison Production Property Public Health Research Infrastructure Research Personnel Resistance Resources Route Safety Sampling Scientist Solubility Source Structure-Activity Relationship Synthesis Chemistry Testing Toxic effect Work analog antimicrobial antimicrobial drug base cytotoxicity design drug discovery effective therapy efficacy testing experience falls fungus high throughput screening improved in vivo metabolomics methicillin resistant Staphylococcus aureus microbial novel pathogen pre-clinical professor research study response scaffold scale up screening small molecule

项目摘要

The Center will apply state-of-the-art genomics and metabolomics approaches to guide the discovery of high value leads produced by under-explored sources of biological diversity. We will focus on compounds that have evolved to be functional through mediation of symbiotic communication between microbes and hosts. The In vitro Core (Core B) scientists will work collaboratively with Professor Bugni's laboratory to produce and purify natural products provided by all three projects in the Center. Core B scientists will assess the anti-microbial activities of extracts, fractions and compounds against drug resistant target pathogens by leveraging the high throughput assay infrastructure and expertise currently available in the UW Small Molecule Screening and Synthesis Facility (SMSSF) and Professor Bugni's laboratory. Doseresponse properties in the antimicrobial assays will be evaluated to prioritize the selection ofthe most potent compounds with broad, cidal activity that causes the death of microbial cells in culture. Compounds with antimicrobial activity then will be assessed for cytotoxicity on primary human cells in order to eliminate toxic compounds early in the projects. Core B scientists also will be responsible for scale-up production of pure compounds (selected by the Center PI and Project leaders) using optimized fermentation approaches developed in Professor Bugni's laboratory and production-scale purification infrastructure. Compounds will be evaluated for stability, solubility and formulation through coordination with the UW School of Pharmacy Pharmaceutical Experiment Station. Sufficient quantities ofthe pure compounds will be provided to Core C for testing the efficacy and safety of the compounds in mice and to Core D, the Mechanism of Action Core. Core B will provide medicinal chemistry expertise to evaluate potential synthetic strategies for simplified analogs and/or for semisynthetic derivatization to improve the pharmacokinetics of scaffolds or determine structure-activity-relationships.

该中心将应用最先进的基因组学和代谢组学方法来指导发现尚未开发的生物多样性来源产生的高价值先导化合物。我们将重点关注通过介导微生物和宿主之间的共生通讯而进化出功能的化合物。体外核心（核心B）科学家将与布尼教授的实验室合作，生产和纯化该中心所有三个项目提供的天然产品。 Core B 科学家将利用华盛顿大学小分子筛选和合成设施 (SMSSF) 和 Bugni 教授实验室现有的高通量检测基础设施和专业知识，评估提取物、级分和化合物对耐药目标病原体的抗菌活性。将评估抗菌测定中的剂量反应特性，以优先选择具有广泛杀灭活性的最有效化合物，这些杀灭活性可导致培养物中的微生物细胞死亡。然后将评估具有抗菌活性的化合物对原代人类细胞的细胞毒性，以便在项目早期消除有毒化合物。核心 B 科学家还将负责使用 Bugni 教授实验室和生产规模纯化基础设施开发的优化发酵方法来扩大纯化合物的生产规模（由中心 PI 和项目负责人选择）。将通过与华盛顿大学药学院制药实验站的协调来评估化合物的稳定性、溶解度和配方。足够数量的纯化合物将提供给Core C，用于测试化合物在小鼠中的功效和安全性，并提供给Core D（作用机制核心）。核心 B 将提供药物化学专业知识，以评估简化类似物和/或半合成衍生化的潜在合成策略，以改善支架的药代动力学或确定结构-活性-关系。