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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未被充分开发的生物多样性来源产生的高价值线索。我们将专注于通过微生物和宿主之间的共生通信而进化成具有功能的化合物。试管核心(核心B)的科学家将与布格尼教授的实验室合作，生产和提纯该中心所有三个项目提供的天然产品。B核心科学家将利用华盛顿大学小分子筛选和合成设施(SMSSF)和布格尼教授的实验室现有的高通量测试基础设施和专业知识，评估提取物、馏分和化合物对耐药目标病原体的抗菌活性。将对抗菌检测中的不同响应特性进行评估，以优先选择具有广泛杀菌活性的最有效化合物，这些化合物会导致培养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。B核心科学家还将使用布格尼教授实验室开发的优化发酵方法和生产规模的纯化基础设施，负责扩大纯化合物的生产(由PI中心和项目负责人选择)。通过与华盛顿大学药学学院药学实验站的协调，将对化合物的稳定性、溶解性和配方进行评估。足够数量的纯化合物将被提供给核心C，用于在小鼠身上测试化合物的有效性和安全性，并提供给核心作用机制核心D。Core 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。