A Small Molecule That Blocks Salmonella Replication in Macrophages

项目概要 微生物病原体如何逃避宿主细胞防御仍不清楚。一个完整的分子 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型化学品 人类病原体。因此，我们开发了一种基于细胞内、高内涵显微镜的筛选 平台（称为 SAFIRE）可识别防止 GFP 积累的化合物 在巨噬细胞中表达肠沙门氏菌鼠伤寒血清型（S. Typhimurium）。我们是 现在正处于建立复合作用机制的阶段，包括定义为什么复合 使巨噬细胞在细菌被杀死的同时存活。我们建议研究的化合物， JD1 尚未充分发展成为药物开发的先导化合物，但已处于领先地位 基本生物学发现阶段。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目标，并可能确定一种化学物质 改进后用作抗菌剂。 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