ADHESIN-BASED NANOTHERAPEUTICS IN URINARY TRACT INFECTION

基于粘附素的纳米疗法治疗尿路感染

基本信息

批准号：
8527763
负责人：
DAVID ALAN HUNSTAD
金额：
$ 29.45万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8527763
关键词：
Acceleration Acute Acute Cystitis Adhesions Adhesives Anti-Bacterial Agents Anti-Infective Agents Antibiotic Therapy Antibiotics Bacteria Bacterial Adhesins Bacterial Infections Bacterial Proteins Binding Biochemical Biochemistry Bladder Bladder Tissue Cancer Vaccines Capsid Proteins Cations Cells Cellular biology Chemicals Chronic Chronic Cystitis Communicable Diseases Communities Comprehension Coupled Cystitis Data Development Devices Electron Microscopy Engineering Environment Epithelial Epithelial Cells Epithelium Escherichia coli Fiber Goals Immunity In Vitro Invaded Knowledge Location Malignant Neoplasms Mediating Medical Microbial Biofilms Modeling Molecular Morbidity - disease rate Mus Oral Pathogenesis Pilum Plague Polymers Population Process Property Proteins Recurrence Resistance Resolution Seeds Series Silver Site Source Specificity Staging Surface Syndrome System Techniques Therapeutic Therapeutic Agents Toxic effect Tumor Cell Derivative Vaccine Urinary tract Urinary tract infection Uropathogenic E. coli Vaccine Antigen Viral Woman Work antimicrobial antimicrobial drug bacterial resistance base carbene cost design exhaustion experience flexibility in vivo microbial nanoparticle nanotherapeutic novel novel therapeutics particle pathogen prevent programs public health relevance receptor residence targeted delivery therapy resistant

项目摘要

DESCRIPTION (provided by applicant): The need for new anti-infective agents and strategies is underscored by recent acceleration in bacterial resistance to existing antibiotics and the exhaustion of currently known targets of microbial cell biology and biochemistry. Further anti-infectives development will be driven by discovery of the pathogenic molecular processes of infectious diseases, which are often initiated by host-pathogen encounters at epithelial surfaces. Urinary tract infections (UTIs), a major source of morbidity and medical costs worldwide, are caused primarily by uropathogenic Escherichia coli, which employ an adhesive fiber termed the type 1 pilus to bind and invade bladder epithelial cells. Recurrences are common after acute UTI, and recent data suggest that bacteria establish chronic residence within bladder tissue, resist oral antibiotic therapy, and re-emerge to cause these recurrences. In this application, we propose to deliver anti-infective agents into epithelial cells via the conjugation of antimicrobial-bearing polymer nanoparticles (NPs) with a bacterial adhesin, a protein that confers epithelial binding and invasion capacity upon our model Gram-negative pathogen. Our first objective will be to refine the chemical processes by which a subject protein (specifically the binding domain of the E. coli type 1 pilus adhesin FimH) can be conjugated with favorable orientation and distribution to the exterior of a series of polymer NPs. Second, we will demonstrate the adhesin-dependent internalization of these functionalized NPs into bladder epithelial cells in vitro and in vivo, providing uniquely available controls to prove the specificity of the adhesin-receptor interaction. Third, we will optimize the loading of silver cation and structurally modifiable silver carbene antimicrobials into the NPs. Finally, we propose to demonstrate the anti-infective activity of these antimicrobial-bearing, adhesin-coupled NPs, both in vitro and in murine models of acute and chronic cystitis caused by uropathogenic E. coli. Advantages of this system include the capability to deliver antimicrobials in high concentration to the intracellular compartment where pathogens may reside, avoidance of toxicities associated with systemic antibiotic and NP administration, and flexibility in the structural design of both the protein "coat" and the antimicrobial passenger. Though we will model the utility of our system using bacterial infection of the mammalian urinary tract, the delivery of pharmacologic agents of choice into selected epithelial cell populations will have broader applications spanning infectious diseases, cancer, and vaccine antigen delivery. PUBLIC HEALTH RELEVANCE: Recurrent urinary tract infection (UTI) plagues many otherwise healthy women and complicates other urinary tract conditions. We propose to develop nanoscopic particles bearing silver-based antibacterial agents and coated with a bacterial protein to confer adhesion to the bladder surface. We will evaluate the ability of these nanoparticles to prevent and treat UTI.

描述（由申请人提供）：最近对现有抗生素的细菌耐药性加速以及当前已知的微生物细胞生物学和生物化学靶标的精疲力尽，对新的抗感染剂和策略的需求强调了。进一步的抗感染性发育将通过发现传染病的致病分子过程来驱动，这些致病性分子过程通常是由上皮表面宿主 - 育毒素遭遇引发的。尿路感染（UTI）是全球发病率和医疗成本的主要来源，主要是由尿路病大肠杆菌引起的，该大肠杆菌采用了粘合剂纤维，称为1型Pilus来结合并入侵膀胱上皮细胞。急性UTI后复发是常见的，最近的数据表明细菌在膀胱组织内建立了慢性居住，抵抗口服抗生素疗法并重新出现会引起这些复发。在此应用中，我们建议通过与细菌粘附素的抗菌聚合物纳米颗粒（NPS）结合将抗感染剂传递到上皮细胞中，该蛋白是一种蛋白质，一种蛋白质，该蛋白质赋予上皮结合和侵入能力与我们的模型革兰氏革兰氏革兰氏革兰氏阴性pation虫。我们的第一个目的是完善受试者蛋白（特别是大肠杆菌1型菌毛粘附素FIMH的结合结构域）的化学过程。其次，我们将在体外和体内证明这些功能化的NP的粘附素依赖性内在化在膀胱上皮细胞中，提供了独特的可用控件，以证明粘附素 - 受体相互作用的特异性。第三，我们将优化银阳离子和结构修改的银碳碳抗菌抗菌剂的负载。最后，我们建议在体外和由尿道病大肠杆菌引起的急性和慢性膀胱炎的鼠模型中证明这些抗菌蛋白偶联的NP的抗感染活性。该系统的优势包括能够高浓度地输送病原体的细胞内室，避免与全身性抗生素和NP给药相关的毒性以及蛋白质“ ACAT”和抗菌剂的结构设计的灵活性。尽管我们将使用哺乳动物尿路的细菌感染对系统的实用性进行建模，但是将选择的药理学剂递送到选定的上皮细胞群体中将具有更广泛的应用，涵盖了传染病，癌症和疫苗抗原递送。公共卫生相关性：经常出现的尿路感染（UTI）困扰着许多其他健康的女性，并使其他尿路状况复杂化。我们建议开发带有银基抗菌剂的纳米粒子，并用细菌蛋白涂层以赋予膀胱表面粘附。我们将评估这些纳米颗粒预防和治疗UTI的能力。