Simultaneous Treatment of Viral and Bacterial Otitis Media Using Plant Natural Products

使用植物天然产品同时治疗病毒性和细菌性中耳炎

基本信息

批准号：
10530599
负责人：
SIJIN LI
金额：
$ 14.66万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10530599
关键词：
Active Sites Acute Affect Alkaloids Anabolism Anti-Bacterial Agents Antibiotic Resistance Antibiotics Antimicrobial Effect Artemisinins Auditory Physiology Bacteria Bacterial Antibiotic Resistance Bacterial Infections Berberine Biochemistry Biological Biological Availability Biological Testing Biology Breeding Cell Membrane Permeability Cells Charge Chemicals Child Child Health Childhood Chinchilla (genus)Collaborations Complex Development Diagnosis Disease Drug Delivery Systems Drug resistance Ear Ear Diseases Effectiveness Engineering Enhancers Enzymes Exhibits Formulation Future Gel Goldenseal Health High Prevalence Human body Hydrogels Hydrophobicity In Vitro Infection Investigation Isoquinolines Knowledge Lead Left Liquid Chromatography Liquid substance Medicinal Plants Methodology Microbe Modeling Modification Molecular Nasopharynx Natural Products Opioid Otitis Media Pathway interactions Permeability Persons Pharmaceutical Preparations Pharmacologic Substance Plants Preparation Production Property Recurrence Research Resistance Site Site-Directed Mutagenesis Speech Development Structure System Techniques Temperature Testing Therapeutic Thick Tissues Treatment Efficacy Treatment outcome Tympanic membrane Tyrosine Universities Viral Virus Virus Diseases Work Yeasts antimicrobial biomaterial compatibility chemical synthesis cytotoxicity design experience in vivo innovation insight knowledge base methicillin resistant Staphylococcus aureus microbiome middle ear molecular size natural product derivative novel pathogenic bacteria permanent hearing loss reconstruction scaffold screening side effect synthetic biology technology development treatment duration

项目摘要

1 Project Summary 2 Otitis media (OM) is a major child health burden. It is the most commonly diagnosed pediatric disease and the 3 #1 reason for antimicrobial prescription to US children. Moreover, 62% of children with OM demonstrate viral 4 infections in their middle ear, to which antibiotics are ineffective but prescribed nonetheless. The widespread use 5 of systemic antibiotics against a disease of such high prevalence and recurrence is believed to breed antibiotic 6 resistance. To treat viral and bacterial infections simultaneously, we will design and synthesize sophisticated 7 plant natural products (PNPs) and their derivatives with no known drug resistance,. The state-of-the-art synthetic 8 biology pipeline that we pioneered will enable the optimization and scalable production of antimicrobial PNPs 9 with enhanced permeability and antimicrobial efficacy. The novel PNP compounds will be delivered locally into 10 the middle ear using a proven hydrogel, which is an easy-to-apply liquid at room temperature and gels quickly 11 and firmly upon contacting warm tympanic membrane (TM). Chemical permeation enhancers inside the gel can 12 overcome the impermeable barrier of the TM and bring the PNPs into the middle ear. We have demonstrated 13 that a single application of the hydrogel formulation provides enough antibiotics for a 7-day treatment, eradicating 14 the infection in a chinchilla OM model. 15 The current application attempts to completely eliminate antibiotic usage in this prevalent childhood disease and 16 to mitigate OM-related drug resistance by using a stand-alone therapy that treats both bacterial and viral 17 infections. It focuses on the production and modification of berberine, an alkaloid derived from medicinal plants. 18 Berberine has demonstrated antimicrobial effects against Gram-positive and -negative bacteria including MRSA 19 and has shown antiviral properties against multiple viruses. This work will leverage our experience in PNP 20 biosynthesis to reconstruct a biosynthetic pathway in yeast for berberine production. We will incorporate diverse 21 tailoring enzymes (e.g., halogenases) and modified precursor molecules to produce modified berberine 22 derivatives that are difficult to achieve by conventional chemical synthesis. The therapeutic efficacy and 23 biocompatibility of the modified berberine derivatives will be tested using an established chinchilla OM model. 24 The knowledge and techniques developed in this project will provide new insight into overcoming the biological 25 barriers in the ear via molecular design and new treatments for acute and recurrent OM. The focus on berberine 26 is based on its known antimicrobial effect, and the general methodologies are applicable to other PNPs that 27 could treat ear diseases beyond OM.

1 项目概要 2 中耳炎 (OM) 是儿童的主要健康负担。它是最常见的儿科疾病， 3 为美国儿童开抗菌药物处方的第一大原因。此外，62% 的 OM 儿童表现出病毒感染 4 例中耳感染，抗生素对其无效，但仍开了处方。广泛使用 5 全身性抗生素针对如此高患病率和复发率的疾病被认为会滋生抗生素 6电阻。为了同时治疗病毒和细菌感染，我们将设计和合成复杂的 7种无已知耐药性的植物天然产物（PNPs）及其衍生物。最先进的合成我们开创的 8 条生物管道将实现抗菌 PNP 的优化和规模化生产 9.具有增强的渗透性和抗菌功效。新型 PNP 化合物将被本地输送至 10 中耳使用经过验证的水凝胶，它是一种在室温下易于涂抹的液体，并能快速凝胶化 11 并牢固地接触温暖的鼓膜（TM）。凝胶内的化学渗透增强剂可以 12 克服 TM 的不可渗透屏障，将 PNP 引入中耳。我们已经证明了 13 单次使用水凝胶制剂即可提供足够的抗生素进行 7 天的治疗，从而根除图14 龙猫OM模型中的感染。 15 目前的应用试图完全消除这种流行的儿童疾病中抗生素的使用，并且 16 通过使用同时治疗细菌和病毒的独立疗法来减轻 OM 相关的耐药性 17 例感染。它专注于小檗碱的生产和修饰，小檗碱是一种从药用植物中提取的生物碱。 18 小檗碱对革兰氏阳性和阴性细菌（包括 MRSA）具有抗菌作用 19 并显示出针对多种病毒的抗病毒特性。这项工作将利用我们在 PNP 方面的经验 20 生物合成重建酵母中小檗碱生产的生物合成途径。我们将融合多元化 21 种剪裁酶（例如卤化酶）和修饰前体分子以产生修饰小檗碱 22种常规化学合成难以获得的衍生物。治疗效果及 23 修饰的小檗碱衍生物的生物相容性将使用已建立的龙猫 OM 模型进行测试。 24 该项目中开发的知识和技术将为克服生物问题提供新的见解。通过分子设计和针对急性和复发性 OM 的新疗法，消除耳朵中的 25 种障碍。关注小檗碱 26 是基于其已知的抗菌作用，一般方法适用于其他 PNP 27 可以治疗 OM 以外的耳部疾病。