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.

项目摘要 细菌病原体使用各种策略来逃避宿主防御并定居 哺乳动物组织。一些细菌逃避宿主免疫系统的各个方面，例如 中性粒细胞和抗体，通过藏在巨噬细胞的内部。但是，巨噬细胞 本身就是好细菌杀手。因此，细菌如何承受 巨噬细胞防御和获得足够的营养以生存甚至复制 仍然是感染生物学的关键问题。我们打算通过 开发新工具来探测巨噬细胞 - 细菌相互作用。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 细胞内病原体沙门氏菌肠肠菌，在鼠类中定居巨噬细胞 伤寒模型。我们最近开发了一种定量，表型，高含量，in- 巨噬细胞筛查的小分子，可防止或增加细菌的生长 巨噬细胞。基于我们的飞行员屏幕，我们预计将确定总共 大约有118个促进肠链球菌的预防和5个小分子 巨噬细胞内的复制。我们建议分析复合化学结构， 评估纯度并建立有效浓度50并表征效果 使用体内成像的感染动力学和细胞形态的化合物。