A Small Molecule That Blocks Salmonella Replication in Macrophages

项目总结 微生物病原体是如何逃避宿主细胞防御的，目前尚不清楚。全分子的 了解宿主与病原体的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的新的化学物质类别 人类病原体。因此，我们开发了一种基于细胞内、高含量显微镜的筛选 平台(称为Safire)，识别防止GFP-积累的化合物- 鼠伤寒沙门氏菌在巨噬细胞中的表达我们是 现在处于建立化合物作用机制的阶段，包括定义为什么化合物 使巨噬细胞在细菌被杀死的同时存活下来。我们计划研究的化合物， Jd1还没有得到充分开发，不能作为药物开发的先导化合物，而是在 基本的生物学发现阶段。这些努力可能会揭示宿主-病原体生物学的新方面， 革兰氏阴性细菌病原体的新靶点，并可能识别一种可能是 改进后可用作抗菌剂。 0

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