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

• 批准号: 10310502
• 负责人: SIJIN LI
• 金额: $ 14.7万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310502
• 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; 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; 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; 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

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个项目摘要 2中耳炎（OM）是主要儿童健康负担。它是最常见的儿科疾病， 3＃1对我们儿童进行抗菌处方的原因。此外，有62％的OM儿童证明了病毒 4中耳感染，抗生素无效，但仍处方。广泛使用 5种针对这种高流行和复发疾病的全身性抗生素被认为繁殖抗生素 6阻力。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植物天然产物（PNP）及其衍生物没有已知的耐药性。最先进的合成 8我们开创的生物学管道将使抗菌PNP的优化和可扩展产生 9具有增强的渗透性和抗菌功效。新颖的PNP化合物将在本地传递到 10中耳使用经过验证的水凝胶，该水凝胶在室温下是一种易于涂上的液体，并迅速凝胶 11并在接触温暖的鼓膜膜（TM）时牢固。凝胶中的化学渗透增强剂可以 12克服TM的不渗透障碍，并将PNP带入中耳。我们已经证明了 13水凝胶配方的单一应用为7天治疗提供了足够的抗生素 14龙猫OM模型中的感染。 15当前的申请试图在这种普遍的儿童疾病中完全消除抗生素的使用和 16通过使用独立治疗细菌和病毒的独立疗法来减轻与OM相关的耐药性 17个感染。它着重于berberine的生产和修饰，berberine是一种源自药用植物的生物碱。 18 Berberine表现出针对革兰氏阳性和负细菌（包括MRSA）的抗菌作用 19并显示了针对多种病毒的抗病毒特性。这项工作将利用我们在PNP中的经验 20生物合成以重建酵母中的生物合成途径以生产berberine。我们将结合多样 21剪裁酶（例如卤代酶）和改良的前体分子可产生改良的小ber碱 22种传统化学合成难以实现的衍生物。治疗功效和 23修改后的berberine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学提供新的见解 通过分子设计和急性和经常性OM的新处理，耳朵中的25个障碍。重点 26基于其已知的抗菌作用，一般方法论适用于其他PNP 27可以治疗OM以外的耳部疾病。