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Development of Nanoparticle Antibiotic Adjuvant for the Treatment of Chronic Suppurative Otitis Media

纳米颗粒抗生素佐剂治疗慢性化脓性中耳炎的开发

基本信息

批准号：
10203796
负责人：
Peter Luke Santa Maria
金额：
$ 19.82万
依托单位：
STANFORD 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：
2020-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10203796
关键词：
Address Adjuvant Adjuvant Therapy Affect Aftercare Animal Model Antibiotics Applications Grants Area Bacteria Bacterial DNA Binding Cell Death Cells Child Chronic Cochlea DNA Repair Data Development Disease Dose Enhancers Fluorescein Fluoroquinolones Foundations Goals Gold Hair Cells Hearing Tests Human In Vitro Industry Standard Infection Labyrinth Lead Measures Mediating Medical Metabolic Methods Microbial Biofilms Modality Modeling Mus Ofloxacin Operative Surgical Procedures Peptides Permeability Pharmaceutical Preparations Phase Phenotype Production Proteins Pseudomonas aeruginosa Reactive Oxygen Species Relapse Research Research Project Grants SOS Response Single-Stranded DNA Small Business Innovation Research Grant Suppurative Otitis Media Testing Therapeutic Time Toxic effect United States National Institutes of Health Work World Health bacterial community cohort effective therapy efficacy evaluation efficacy study hearing impairment hydrophilicity in vivo ineffective therapies inhibitor/antagonist middle ear multidrug-resistant Pseudomonas aeruginosa nanocluster nanoparticle novel novel therapeutics ototoxicity permanent hearing loss pre-clinical prevent success

项目摘要

Project Summary / Abstract We request NIH support to investigate the use of functionalized gold nanoclusters as an adjuvant therapy for chronic suppurative otitis media (CSOM). CSOM is characterized by a chronically discharging infected middle ear that is most frequently caused by Pseudomonas aeruginosa (PA) and is a leading cause of permanent hearing loss. In CSOM, PA exists in bacterial communities known as biofilms. Fluoroquinolone eardrops are the primary method of treatment due to its non-ototoxicity. However, this treatment is ineffective in fully eradicating the infection. This is a result of the inability of fluoroquinolone to target a subpopulation of metabolically inactive bacteria known as persister cells within the biofilms. Persister cells repopulate the biofilm niche after therapy is discontinued, causing a relapse of CSOM. The end result is multiple rounds of surgery and a lifelong struggle with this disease. There is a large unmet medical need to develop new medical therapies aimed at persister cells in biofilms of CSOM. Our lab has recently created and validated a novel PA CSOM animal model with bioluminescent strains of PA allowing real time tracking of disease. It mimics the human condition by persisting beyond six months, is recalcitrant to topical fluoroquinolone therapy, and leads to hair cell death (i.e. hearing loss) over time. Using our unique model of PA CSOM, we are now able to test novel therapeutics for CSOM. Consequently, we have created an anionic hydrophilically functionalized gold nanocluster covalently conjugated with cell penetrating peptide (AuNC@CPP) as an adjuvant for fluoroquinolones. We have shown, in vitro, that co-administration of the AuNC@CPP with ofloxacin completely eliminates persister cells in both stationary phase and biofilms of PA. The exceptional killing ability of AuNC@CPP plus ofloxacin opens up the possibility to develop the first therapeutic that specifically targets PA CSOM. We theorize that our AuNC@CPP combined with ofloxacin therapy can eradicate PA CSOM in vivo. Because our preliminary data shows that AuNC@CPP does not increase intracellular ofloxacin concentration, we hypothesize that AuNC@CPP acts as both an enhancer of reactive oxygen species (ROS)-mediated ofloxacin lethality and inhibits bacterial DNA repair. We propose to determine the mechanism(s) behind how AuNC@CPP potentiates ofloxacin lethality of persister cells by measuring intracellular ROS production and evaluating RecA inhibition followed by in vivo studies for efficacy and ototoxicity in comparison to ofloxacin alone. The proposed work will develop the first adjuvant therapy that specifically targets recalcitrant CSOM and lays the foundation for future research of this treatment in other chronic biofilm infections.

项目摘要/摘要