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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：
10115426
负责人：
SIJIN LI
金额：
$ 14.72万
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 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10115426
关键词：
Active Sites Acute Affect Alkaloids Anabolism Anti-Bacterial Agents Antibiotic Resistance Antibiotics Antimicrobial Effect Antiviral Agents Artemisinins Auditory Physiology Bacteria Bacterial Antibiotic Resistance Bacterial Infections Berberine Biochemistry Biological Biological Availability Biological Testing Biology 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 Natural Products Opioid Otitis Media Pathway interactions Permeability 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 Yang Yeasts antimicrobial base biomaterial compatibility chemical function chemical synthesis cytotoxicity design experience in vivo innovation insight knowledge base methicillin resistant Staphylococcus aureus microbiome middle ear molecular size novel pathogenic bacteria permanent hearing loss reconstruction scaffold screening side effect synthetic biology 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项目概述