TB Phage therapy: Optimizing delivery methods of mycobacteriophages to target intracellular Mycobacterium tuberculosis

结核菌噬菌体疗法：优化分枝杆菌噬菌体的递送方法以靶向细胞内结核分枝杆菌

• 批准号: 10312824
• 负责人: WILLIAM Robert JACOBS
• 金额: $ 21万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-07 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312824
• 关键词: Abscess; Address; Aerosols; Antibiotic Therapy; Awareness; Bacillus; Bacterial Infections; Bacteriophages; C3HeB/FeJ Mouse; Capsid Proteins; Cause of Death; Cell membrane; Cells; Cessation of life; Clinical; Drug resistance; Drug usage; Effectiveness; Engineering; Environment; Epidemic; Equus caballus; Frequencies; Genetic; Goals; Grant; HIV; Human; Immunosuppression; In Vitro; Infection; Ligands; Lung; Lytic; Mediating; Methods; Mus; Mycobacteriophages; Mycobacterium Infections; Mycobacterium smegmatis; Mycobacterium tuberculosis; Organism; Phage Display; Pharmaceutical Preparations; Pharmacotherapy; Powder dose form; Proteins; Regimen; Reporter; Reporting; Resistance; Resistance development; Resources; Rifampicin resistance; Site; Testing; Therapeutic Agents; Time; Tuberculosis; Vaccines; Virus; Work; aerosolized; base; chemotherapy; delivery vehicle; experience; fighting; global health; improved; interest; macrophage; mouse model; novel strategies; novel therapeutics; pathogen; pressure; prevent; resistant strain; success; tool; treatment duration; treatment optimization; tuberculosis chemotherapy; tuberculosis drugs; tuberculosis treatment; uptake

Abstract Tuberculosis (TB) remains as a major global health problem causing 1.2 million deaths and over 10 million new cases each year. The onset of the HIV epidemic beginning in the late 1980s led to immune suppression in humans and significantly increased the emergence of drug resistance, lengthening treatment duration. Ominously, there are strains of M. tuberculosis, the causative agent of TB, that are resistant to many, if not all, of the currently available TB drugs that are extremely difficult to treat. As an alternative to drugs, mycobacteriophages - viruses that kill M. tuberculosis, have been considered as possible agents to treat tuberculosis. However, previous studies have had limited success in mammalian hosts. The goal of this grant is to elucidate why phage therapy fails to work. We hypothesized that the major obstacle is mycobacteriophages are unable to come into contact with the M. tuberculosis cells that live intracellularly. We propose to develop novel strategies to deliver mycobacteriophages to the intracellular compartments in which M. tuberculosis resides. One approach would be to engineer mycobacteriophage capsid proteins so that we can add macrophage delivery ligands to promote cellular uptake. In addition, we plan to explore the use of a Mycobacterium smegmatis strain as a Trojan horse delivery vector to the intracellular M. tuberculosis. These studies will be enhanced by our ability to generate mycobacteriophages that express fluorescent reporter proteins. In order to deliver the mycobacteriophages to the lungs, the site of intracellular localization, we plan to use spray dried mycobacteriophage powders. We also plan to test the hypothesis that mycobacteriophages may work as an adjunct therapy with existing TB drugs in mouse models.

摘要 结核病（TB）仍然是一个主要的全球健康问题，造成120万人死亡，1000多人死亡。 每年新增100万例。20世纪80年代末开始的艾滋病毒流行病的爆发导致了免疫 抑制在人类和显着增加耐药性的出现，延长 治疗持续时间。不幸的是，有M.结核病，结核病的病原体， 对许多（如果不是全部）目前可用的结核病药物具有耐药性，这些药物极难治疗。 药物的替代品，分枝杆菌噬菌体-杀死M的病毒。结核病被认为是 治疗肺结核的可能药物。然而，以前的研究在哺乳动物中的成功有限。 hosts.这项资助的目的是阐明为什么噬菌体疗法不起作用。我们假设 主要障碍是分枝杆菌噬菌体不能与M.结核细胞 它们生活在细胞内我们建议开发新的策略，将分枝杆菌噬菌体递送到 胞内区室中，M.肺结核的存在。一种方法是设计 因此，我们可以添加巨噬细胞递送配体，以促进细胞 摄取。此外，我们计划探索使用耻垢分枝杆菌菌株作为特洛伊木马 递送载体至细胞内M.结核这些研究将通过我们的能力得到加强， 产生表达荧光报告蛋白的分枝杆菌噬菌体。以便为您提供这些 分枝杆菌噬菌体的肺部，细胞内定位的网站，我们计划使用喷雾干燥 分枝杆菌噬菌体粉末。我们还计划测试分枝杆菌噬菌体可能作为 在小鼠模型中使用现有结核病药物的辅助治疗。