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High content, high throughput, diversity screen for novel anti-tubercular agents targeting intracellular bacteria

针对细胞内细菌的新型抗结核药物的高含量、高通量、多样性筛选

基本信息

批准号：
10526217
负责人：
Tanya Parish
金额：
$ 29.54万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-12 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10526217
关键词：
Address Antibiotics Antitubercular Agents Bacteria Bacterial Infections Biological Biological Assay Cell Survival Cells Cessation of life Chemicals Communicable Diseases Data Development Diversity Library Drug resistance in tuberculosis Eukaryotic Cell Evaluation Future Generations HIV Heterogeneity Host Defense Mechanism Human Infection Lead Location Methods Monitor Mycobacterium tuberculosis New Agents Outcome Penetration Persons Pharmaceutical Preparations Pharmacotherapy Phenotype Physiological Population Property Regimen Running Series Time Tuberculosis Work antibiotic tolerance axenic culture base counterscreen drug discovery drug-sensitive global health inhibitor interest macrophage mycobacterial new therapeutic target novel novel therapeutics pathogen screening small molecule libraries success targeted agent tuberculosis drugs tuberculosis treatment

项目摘要

Summary Tuberculosis remains a major global health burden with 10 million new cases in 2019 and a latently-infected population of billions. Deaths from tuberculosis now exceed those from HIV (1.2 million in 2019). Mycobacterium tuberculosis, the causative agent, is a sophisticated pathogen which can persist for decades in the human host and which requires lengthy treatment for cure with multiple antibiotics. One of the features of M. tuberculosis is its ability to survive and replicate inside human cells, including macrophages, one of the normal host defense mechanisms against infection. Intracellular bacteria are a specific population which can be hard to kill, in part due to the requirement that molecules enter eukaryotic cells, and in part due to the different physiological state in which the bacteria persist. Increasing evidence points to a higher level of antibiotic tolerance in intracellular bacteria, as well as increased heterogeneity. In order to find new agents, we developed a phenotypic screening method utilizing high content screening to monitor bacterial and eukaryotic cell survival simultaneously. We ran a pilot screen to identify novel chemical inhibitors of mycobacterial intracellular replication. We found several series of interest and selected three series with attractive physicochemical properties. Based on our initial success we propose to expand our effort to run a larger diverse screening set. The overall aim of this proposal is to screen a diversity set of molecules against intracellular Mtb and to evaluate and prioritize hits for future work. We will combine biological activity, profile, mode of action and physicochemical properties to select series with the most promise. The major outcome of this exploratory proposal will be novel chemical matter ready to enter the discovery pipeline.

总结