Engineering probiotics for tuberculosis therapy

用于结核病治疗的工程益生菌

基本信息

批准号：
10629371
负责人：
Tal Danino
金额：
$ 23.39万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
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：
2022-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629371
关键词：
3-Dimensional Antibiotics Antimycobacterial Agents Automobile Driving Bacteria Biological Assay Cells Cessation of life Coculture Techniques Combined Antibiotics Complement Coupling Cutaneous Data Disease Drug Delivery Systems Drug resistance Engineered Probiotics Engineering Environment Escherichia coli Euthanasia Genetic Genetic Engineering Genetic Programming Genus Mycobacterium Granuloma Granulomatous Granulomatous disease Growth Histologic Home Hypoxia Immune response In Vitro Individual Infection Infiltration Intelligence Libraries Macrophage Measures Medicine Microbe Microscopy Modeling Molecular Monitor Mus Mycobacterium Infections Mycobacterium marinum Mycobacterium tuberculosis Necrosis Organ Pathogenicity Pathologic Peptides Persons Predisposition Probiotics Production Proliferating Proteins Recombinants Reporter Reporter Genes Resistance Safety Site Solid Neoplasm Specificity T-Lymphocyte Techniques Testing Therapeutic Therapeutic Agents Time Tissues Toxic effect Treatment Efficacy Tuberculosis Virulent Work antimicrobial cancer therapy clinically relevant delivery vehicle density design draining lymph node in vivo in vivo imaging system interest mouse model mycobacterial neutrophil novel novel strategies pathogen safety testing small molecule synergism synthetic biology therapeutic candidate therapeutic evaluation therapeutic protein tool treatment duration tuberculosis granuloma tuberculosis treatment tumor tumor microenvironment two-dimensional

项目摘要

PROJECT SUMMARY The engineering of living cells and microbes is driving a new era of medicine. This transformative approach allows for the genetic programming of living cells to intelligently sense and respond healthy and diseased envi- ronments in the body. Bacteria have specifically generated significant recent interest due to their genetic tracta- bility and ability to infiltrate disease sites. A multitude of studies have shown bacterial delivery of therapeutic payloads selectively into tumor cores, demonstrating specificity and efficacy that is otherwise unattainable with molecular-based therapeutics. Given this paradigm in cancer therapy, bacteria present a unique opportunity to be engineered as intelligent delivery vehicles to inaccessible disease sites. We recently discovered that probiotic E. coli Nissle 1917 (EcN) selectively home to granulomas, pathological regions developed at infection sites including tuberculosis. Tuberculosis kills 1.5 million people each year but conventional antibiotics are limited by toxicity, long treatment courses, and drug resistance. Importantly, while difficult for conventional therapeutics to reach, granulomas possess unique necrotic and hypoxic microenviron- ment similar to tumors that supports selective bacterial colonization. The objective of this proposal is to engineer EcN to home to granulomas and locally produce therapeutics to eliminate pathogenic Mycobacterium tuberculosis. We will use synthetic biology approaches to genetically engi- neer EcN as an intelligent drug delivery vehicle. We will utilize hypoxia-sensing growth circuits that further restrict probiotic growth the hypoxic, necrotic granuloma environment. Using a novel in vitro 3D coculture assay, we will screen a library of antimicrobial proteins to identify the most potent antimycobacterial therapeutic candidates. We will test the therapeutic efficacy of engineered E. coli using mycobacterium granuloma mouse models. This fundamentally new approach to granulomatous disease will open up opportunities to utilize engineered bacteria as therapeutic agent for granulomatous infections.

项目摘要活细胞和微生物的工程正在推动医学的新时代。这种变革性的方法允许活细胞的遗传编程智能地感知并反应健康和患病的环境体内的隆起。细菌由于其遗传拖拉而明确引起了最近的近期兴趣能力和渗透疾病部位的能力。大量研究表明了治疗的细菌递送有效载荷有选择性地进入肿瘤内核，表明特异性和功效是无法实现的基于分子的治疗剂。鉴于这种癌症治疗中的范式，细菌为将其作为智能运输车辆设计为无法访问的疾病部位。我们最近发现益生菌大肠杆菌Nissle 1917（ECN）有选择地拥有颗粒，病理学在包括结核病在内的感染部位发展的地区。结核病每年杀死150万人，但常规的抗生素受到毒性，长期治疗课程和耐药性的限制。重要的是，而常规治疗剂很难达到，肉芽瘤具有独特的坏死和低氧微环体 - 类似于支持选择性细菌定植的肿瘤。该提案的目的是设计ECN到家为肉芽瘤，并在当地生产治疗剂消除致病性分枝杆菌结核病。我们将使用合成生物学方法来进行基因工程 NEER ECN作为智能药物输送工具。我们将利用低氧感应增长电路，进一步限制益生菌生长低氧，坏死肉芽肿环境。使用小说中的体外3D共培养分析，我们将筛选抗菌蛋白的库，以识别最有效的抗菌治疗候选。我们将使用分枝杆菌小鼠模型测试工程大肠杆菌的治疗功效。这从根本上讲，新的肉芽肿性疾病方法将为使用工程细菌提供机会作为肉芽肿感染的治疗剂。