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：
8321543
负责人：
DAVID ALAN HUNSTAD
金额：
$ 30.53万
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/8321543
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）：最近细菌对现有抗生素的耐药性的加速以及目前已知的微生物细胞生物学和生物化学靶标的耗尽，强调了对新的抗感染剂和策略的需求。传染病致病分子过程的发现将推动抗感染药物的进一步发展，这些过程通常是由上皮表面宿主与病原体的相遇引发的。尿路感染 (UTI) 是全球发病率和医疗费用的主要来源，主要由尿路致病性大肠杆菌引起，该大肠杆菌使用一种称为 1 型菌毛的粘合纤维来结合并侵入膀胱上皮细胞。急性尿路感染后复发很常见，最近的数据表明细菌在膀胱组织内长期驻留，抵抗口服抗生素治疗，并重新出现导致这些复发。在此应用中，我们建议通过将抗菌聚合物纳米颗粒（NP）与细菌粘附素（一种赋予我们的模型革兰氏阴性病原体上皮结合和侵袭能力的蛋白质）结合，将抗感染药物递送到上皮细胞中。我们的首要目标是完善化学过程，通过该过程，主题蛋白（特别是大肠杆菌 1 型菌毛粘附素 FimH 的结合域）可以以有利的方向和分布结合到一系列聚合物纳米粒子的外部。其次，我们将在体外和体内证明这些功能化纳米粒子依赖粘附素内化到膀胱上皮细胞中，提供独特的可用对照来证明粘附素-受体相互作用的特异性。第三，我们将优化银阳离子和结构可修饰的银卡宾抗菌剂在纳米颗粒中的负载。最后，我们建议在体外和尿路病原性大肠杆菌引起的急性和慢性膀胱炎小鼠模型中证明这些带有抗菌剂、粘附素偶联的纳米粒子的抗感染活性。该系统的优点包括能够将高浓度的抗菌药物输送到病原体可能驻留的细胞内区室，避免与全身抗生素和NP给药相关的毒性，以及蛋白质“外壳”和抗菌乘客的结构设计的灵活性。尽管我们将使用哺乳动物泌尿道的细菌感染来模拟我们系统的效用，但将所选药物递送到选定的上皮细胞群中将具有更广泛的应用，涵盖传染病、癌症和疫苗抗原递送。公共卫生相关性：复发性尿路感染 (UTI) 困扰着许多原本健康的女性，并使其他尿路疾病复杂化。我们建议开发带有银基抗菌剂并涂有细菌蛋白的纳米粒子，以赋予膀胱表面粘附力。我们将评估这些纳米粒子预防和治疗尿路感染的能力。