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仍不清楚。完整分子 了解宿主-病原体相互作用将有助于开发新的治疗方法， 感染特别需要确定针对革兰氏阴性菌的新化学品类别 人类病原体因此，我们开发了一种细胞内，高内容显微镜为基础的筛选 平台（称为SAFIRE），该平台鉴定了防止GFP积累的化合物- 表达肠道沙门氏菌血清型鼠伤寒沙门氏菌（S.鼠伤寒沙门氏菌）。我们 目前正处于建立化合物作用机制的阶段，包括确定化合物 使巨噬细胞能够在细菌被杀死的同时存活。我们要研究的化合物， JD 1尚未充分开发，无法成为药物开发的先导化合物，但已处于 基础生物学发现阶段。这些努力可能揭示宿主-病原体生物学的新方面， 革兰氏阴性细菌病原体的新靶点，并可能确定一种化学物质， 改进后用作抗菌剂。 0