Chemical Probes for Bacteria-Macrophage Interactions

用于细菌-巨噬细胞相互作用的化学探针

• 批准号: 9171993
• 负责人: Corrella S Detweiler
• 金额: $ 19.24万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9171993
• 关键词: Accelerometer; Anti-Bacterial Agents; Antibodies; Bacteria; Biological Assay; Biology; Cell Culture Techniques; Cells; Cellular Morphology; Chemical Structure; Chemicals; Colony-Forming Units Assay; Colony-forming units; Data; Development; Dextrans; Diversity Library; Dose; Future; Goals; Growth; Host Defense; Hour; Housing; Immune system; Indoles; Infection; Knowledge; Label; Libraries; Life; Light; Maintenance; Microscopy; Modeling; Monitor; Mus; Nutrient; Phagosomes; Pharmaceutical Preparations; Process; Property; Reporter; Salmonella; Salmonella enterica; Skeleton; Structure; Time; Tissues; Toxic effect; Typhoid Fever; Vacuole; Work; base; dosage; in vivo imaging; killings; liquid chromatography mass spectrometry; macrophage; neutrophil; pathogen; prevent; response; small molecule; tool

PROJECT SUMMARY Bacterial pathogens use diverse strategies to evade host defenses and colonize mammalian tissues. Some bacteria evade aspects of the host immune system, such as neutrophils and antibodies, by hiding inside of macrophages. Macrophages, however, are good bacterial killers in their own right. Therefore, how bacteria withstand macrophage defenses and acquire sufficient nutrients to survive and even replicate remains a key question in infection biology. We intend to close this knowledge gap by developing new tools to probe macrophage-bacterial interactions. Some of these tools could become the basis of antibacterial treatments. We study the Gram-negative intracellular pathogen Salmonella enterica, which colonizes macrophages in a murine typhoid fever model. We recently developed a quantitative, phenotypic, high content, in- macrophage screen for small molecules that prevent or increase bacterial growth inside of macrophages. Based on our pilot screen, we anticipate identifying a total of approximately 118 small molecules that prevent and 5 that promote S. enterica replication within macrophages. We propose to analyze compound chemical structure, evaluate purity, and establish the Effective Concentration50 and characterize the effect of compounds on infection dynamics and cell morphology using in vivo imaging.

项目总结 细菌病原体使用不同的策略来逃避宿主的防御并定植 哺乳动物组织。一些细菌逃避宿主免疫系统的某些方面，例如 中性粒细胞和抗体，通过隐藏在巨噬细胞内。然而，巨噬细胞， 它们本身就是很好的杀菌剂。因此，细菌如何抵御 巨噬细胞防御并获得足够的营养以生存甚至复制 仍然是感染生物学中的一个关键问题。我们打算通过以下方式缩小这一知识差距 开发探测巨噬细胞-细菌相互作用的新工具。其中一些工具 可能成为抗菌治疗的基础。我们研究革兰氏阴性杆菌 在小鼠体内定植巨噬细胞的细胞内病原体肠沙门氏菌 伤寒模型。我们最近开发了一种定量的、表型的、高含量的，在- 巨噬细胞筛选防止或促进细菌生长的小分子 巨噬细胞。根据我们的飞行员屏幕，我们预计将识别总共 大约118个小分子预防肠杆菌感染，5个促进肠杆菌感染 巨噬细胞内的复制。我们建议分析化合物的化学结构， 评估纯度，建立有效浓度50并表征效果 利用体内成像技术研究化合物对感染动力学和细胞形态的影响。