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.

项目概要活细胞和微生物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基因编程智能地感知和响应健康和患病的环境体内的环境。由于细菌的遗传特征，细菌最近引起了人们的极大兴趣能力和渗透疾病部位的能力。大量研究表明细菌可以传递治疗药物有效负载选择性地进入肿瘤核心，展示了其他方法无法达到的特异性和功效基于分子的疗法。鉴于癌症治疗的这种范例，细菌提供了一个独特的机会被设计为智能输送工具到难以到达的疾病地点。我们最近发现，益生菌大肠杆菌 Nissle 1917 (EcN) 选择性地产生肉芽肿、病理性肉芽肿和病理性肉芽肿。包括结核病在内的感染部位出现的区域。结核病每年夺去 150 万人的生命，但传统抗生素受到毒性、疗程长和耐药性的限制。重要的是，虽然传统疗法难以达到，肉芽肿具有独特的坏死和缺氧微环境类似于支持选择性细菌定植的肿瘤。该提案的目标是设计 EcN 使其成为肉芽肿的宿主，并在本地生产治疗药物消除致病性结核分枝杆菌。我们将使用合成生物学方法来进行基因工程 EcN 不再是一种智能药物输送工具。我们将利用缺氧感应生长回路进一步限制益生菌在缺氧、坏死肉芽肿的环境中生长。使用新型体外 3D 共培养测定，我们将筛选抗菌蛋白库，以确定最有效的抗分枝杆菌治疗候选药物。我们将使用肉芽分枝杆菌小鼠模型来测试工程大肠杆菌的治疗效果。这治疗肉芽肿性疾病的全新方法将为利用工程细菌提供机会作为肉芽肿感染的治疗剂。