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A Novel Screen for Antibacterials that Are Non-Toxic to Mammals

一种对哺乳动物无毒的抗菌药物的新型筛选

基本信息

批准号：
9186486
负责人：
Corrella S Detweiler
金额：
$ 22.52万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9186486
关键词：
Alpha Cell Anti-Bacterial Agents Antibiotics Antimicrobial Resistance Bacteria Biochemical Biological Assay Cell membrane Cells Chemosensitization Collection Disease Diversity Library Dose Drug Kinetics Face Goals Gram-Negative Bacteria Growth Human Lead Mammalian Cell Mammals Manufacturer Name Membrane Potentials Modeling Molecular Target Monitor Morbidity - disease rate Multi-Drug Resistance Mus Pharmaceutical Preparations Phase Phylogenetic Analysis Preparation Property Protocols documentation Resistance Salmonella Structure-Activity Relationship System Systemic infection Testing Toxic effect Trees Virulence Virulence Factors Virulent analog bacterial genetics bacterial resistance base cell type cytokine cytotoxicity in vivo indexing macrophage mitochondrial membrane mortality novel novel therapeutics pathogen prevent public health relevance quantitative imaging response scaffold screening small molecule therapeutic target

项目摘要

DESCRIPTION (provided by applicant): There is a critical need for novel therapeutics to treat antimicrobial-resistant Gram-negative bacteria. Historically, antibiotics were identified in screen using whole bacteria. Over the past 20 years, there has instead been intensive biochemical screening that targets bacterial molecules, an approach that has often identified compounds with significant barriers in either the pathogen or the mammalian host, including an inability to enter or remain within host or pathogen cells, destruction by the host or pathogen, or host cytotoxicity. We have therefore developed a quantitative, image-based high content screen that excludes compounds with undesirable properties because it uses whole, virulent, bacteria growing within mammalian cells. We propose to use this screen to identify therapeutics that target nonessential bacterial virulence factors and will be effective against antimicrobial-resistant bacteria.

描述（由申请人提供）：迫切需要新的治疗剂来治疗抗微生物剂耐药性革兰氏阴性菌。历史上，抗生素是使用全细菌在筛选中鉴定的。在过去的20年里，有针对细菌分子的密集的生化筛选，这种方法经常识别出在病原体或哺乳动物宿主中具有显著屏障的化合物，包括无法进入或留在宿主或病原体细胞内，被宿主或病原体破坏，或宿主细胞毒性。因此，我们开发了一种定量的、基于图像的高内容筛选，该筛选排除了具有不良性质的化合物，因为它使用了在哺乳动物细胞内生长的完整的、有毒的细菌。我们建议使用这种筛选来确定针对非必需细菌毒力因子的治疗方法，并对抗生素耐药细菌有效。