A Small Molecule That Blocks Salmonella Replication in Macrophages

阻止沙门氏菌在巨噬细胞中复制的小分子

• 批准号: 10312125
• 负责人: Corrella S Detweiler
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-07 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312125
• 关键词: Affect; Anti-Bacterial Agents; Bacteria; Biological; Biology; Cell membrane; Cells; Chemicals; Colony-forming units; Constitution; Data; Development; Dose; Eukaryotic Cell; Future; Growth; Infection; Lead; Lighting; Lipids; Liposomes; Mammalian Cell; Measurement; Membrane; Membrane Biology; Membrane Fluidity; Microscopy; Molecular; Monitor; Morbidity - disease rate; Morphology; Mus; Phagosomes; Pharmaceutical Preparations; Property; Respiration; Salmonella; Salmonella typhimurium; Spleen; Structure; Testing; Toxic effect; Transmission Electron Microscopy; antimicrobial; base; drug development; experimental study; fluorescence imaging; human pathogen; improved; in vivo; macrophage; mitochondrial membrane; mortality; novel strategies; pathogen; pathogenic bacteria; pathogenic microbe; preference; prevent; screening; small molecule; tool; vesicular release; voltage

PROJECT SUMMARY How microbial pathogens evade host cellular defenses remains unclear. A full molecular understanding of host-pathogen interactions will aid in the development of new approaches to treat infection. There is a particular need to identify new classes of chemicals that target Gram-negative human pathogens. We therefore developed an in-cell, high content microscopy-based screening platform (called SAFIRE) that identifies compounds which prevent the accumulation of GFP- expressing Salmonella enterica serovar Typhimurium (S. Typhimurium) in macrophages. We are now at the stage of establishing compound mechanism of action, including defining why compounds enable the macrophage to survive while the bacterium is killed. The compound we propose to study, JD1, is not sufficiently developed to be a lead compound for drug development but is instead at the stage of basic biological discovery. These efforts may reveal new facets of host-pathogen biology, new targets for Gram-negative bacterial pathogens, and possibly identify a chemical that could be improved for use as an antimicrobial. 0

项目摘要 微生物病原体如何逃避宿主细胞防御尚不清楚。完整的分子 了解宿主病原体相互作用将有助于开发新方法 感染。特别需要识别靶向革兰氏阴性的新类化学物质 人类病原体。因此，我们开发了基于高含量显微镜的筛选 平台（称为Safire），该平台识别可防止GFP-积累的化合物 在巨噬细胞中表达沙门氏菌的血清鼠伤寒（S. typhimurium）。我们是 现在正处于建立复合作用机理的阶段，包括定义为什么化合物 使巨噬细胞在细菌被杀死时能够生存。我们建议研究的化合物， JD1，不足以发展为药物开发的铅化合物，而是在 基本生物学发现的阶段。这些努力可能揭示了宿主生物生物学的新方面， 革兰氏阴性细菌病原体的新靶 改进了作为抗菌剂。 0