Optimizing anti-virulence compounds for the treatment of UTIs

优化用于治疗尿路感染的抗毒力化合物

基本信息

批准号：
8525523
负责人：
SARAH Elizabeth GREENE
金额：
$ 2.85万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8525523
关键词：
Accounting Adhesions Adhesives Adverse effects Affect Antibiotic Resistance Bacteria Bacterial Adhesins Binding Biological Assay Biological Models Bladder Cells Chronic Cystitis Data Development Drug Targeting Environment Epithelial Epithelium Exposure to Fimbriae Proteins Genes Genetic Transcription Genome Growth Hemagglutination Human Infection Invaded Klebsiella pneumonia bacterium Lead Mannose Mediating Medical Membrane Meningitis Microarray Analysis Microbial Biofilms Molecular Chaperones Mutagenesis Mutation N-terminal Neonatal Operon Organelles Organism Pathway interactions Pharmaceutical Preparations Pilum Prophylactic treatment Pyelonephritis Recurrence Regulation Reporter Resistance Retreatment Signal Transduction Surface System Therapeutic Uses Tissues Ureter Urinary tract Urinary tract infection Urine Uropathogen Uropathogenic E. coli Virulence Woman Work antimicrobial community-acquired UTI design effective therapy experience extracellular innovation lifetime risk mutant nosocomial UTI novel strategies novel therapeutics pathogen periplasm pressure prevent promoter public health relevance research study response small molecule

项目摘要

DESCRIPTION (provided by applicant): Urinary tract infections are extremely common infections, affecting 50% of women in their lifetime, with many of these women experiencing recurrent infections. 80% of community acquired UTIs and 50% of nosocolial UTIs are caused by uropathogenic E. coli (UPEC). The increasing rates of antibiotic resistance in UPEC necessitate the development of novel therapeutics to treat these infections. UPEC uses the adhesive extracellular organelle type 1 pili to bind to mannose on the bladder epithelium, allowing the bacteria to attach and invade host cells and establish infection. In addition to type 1 pili, UPEC encode many homologous types of pili, including P and S pili, which are both also associated with UTIs. As our lab has elucidated the details of pilus assembly for these homologous types of pili, we were able to develop small molecules, rationally designed to disrupt pilus assembly. These anti-virulence compounds, termed pilicides, provide a novel approach for the treatment of UTIs, as preventing pilus assembly or function should lessen the virulence of UPEC, or other gram-negative pathogens encoding homologous pili. Therefore, we propose to study the efficacy of pilicides in disrupting assembly of all homologous pili in the UPEC strain UTI89, as well as in other uropathogens. Because these pili are often coordinately regulated, we will also examine the effects of pilicide on the expression of these pili. Furthermore, as pilus expression is affected by environmental signals, we will assess the expression of these pili and the function of pilicides in host-like environments, such as after growth in urine or attachment to human ureter tissue. We also have evidence that pilicides have other effects on UPEC in addition to disrupted pilus assembly. Using microarrays, we will elucidate these pilicide effects, such that we can understand all mechanisms of pilicide action. These studies will increase our understanding of pilicide effects on UPEC pili and allow us to further optimize these compounds for therapeutic use in treating UTIs.

描述（由申请人提供）：尿路感染是极其常见的感染，影响 50% 的女性一生，其中许多女性会反复感染。 80% 的社区获得性尿路感染和 50% 的医院结肠尿路感染是由尿路致病性大肠杆菌 (UPEC) 引起的。 UPEC 中抗生素耐药性的增加需要开发新的疗法来治疗这些感染。 UPEC 使用粘附细胞外细胞器 1 型菌毛与膀胱上皮上的甘露糖结合，使细菌附着并侵入宿主细胞并建立感染。除了类型 1 菌毛，UPEC 编码许多同源菌毛类型，包括 P 菌毛和 S 菌毛，它们也与尿路感染相关。由于我们的实验室已经阐明了这些同源类型菌毛的菌毛组装细节，因此我们能够开发出经过合理设计的小分子来破坏菌毛组装。这些抗毒力化合物，称为杀菌剂，为治疗尿路感染提供了一种新方法，因为防止菌毛组装或功能应减轻 UPEC 或编码同源菌毛的其他革兰氏阴性病原体的毒力。因此，我们建议研究pilicides在破坏UPEC菌株UTI89以及其他尿路病原体中所有同源菌毛组装方面的功效。由于这些菌毛通常受到协调调节，我们还将研究 pilicide 对这些菌毛表达的影响。此外，由于菌毛表达受到环境信号的影响，我们将评估这些菌毛的表达和杀菌剂在类宿主环境中的功能，例如在尿液中生长或附着在人类输尿管组织上后。我们还有证据表明，除了破坏菌毛组装之外，pilicides 对 UPEC 还具有其他影响。使用微阵列，我们将阐明这些 pilicide 效应，以便我们能够了解 pilicide 作用的所有机制。这些研究将增加我们对 UPEC 菌毛作用的了解，并使我们能够进一步优化这些化合物，用于治疗尿路感染。