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

• 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
• 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

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）：尿路感染是非常常见的感染，影响50%的妇女在其一生中，其中许多妇女经历反复感染。 80%的社区获得性尿路感染和50%的医院性尿路感染是由尿路致病性大肠杆菌引起的。大肠杆菌（UPEC）。 UPEC中抗生素耐药性的增加需要开发新的治疗方法来治疗这些感染。UPEC利用粘附性细胞外细胞器1型皮利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皮利，UPEC编码许多同源类型的皮利，包括P和S皮利，它们也与UTI相关。 由于我们的实验室已经阐明了这些同源类型的皮利的菌毛组装细节，我们能够开发出合理设计的小分子来破坏菌毛组装。 这些抗毒性化合物（称为杀菌毛剂）提供了治疗UTI的新方法，因为防止菌毛组装或功能应降低UPEC或编码同源皮利的其它革兰氏阴性病原体的毒性。因此，我们建议研究杀菌毛剂在破坏UPEC菌株UTI 89以及其他尿路病原体中所有同源皮利组装中的功效。 因为这些皮利通常是协调调节的，我们也将研究杀菌毛剂对这些皮利表达的影响。 此外，由于菌毛表达受环境信号的影响，我们将评估这些皮利的表达和杀菌毛剂在宿主样环境中的功能，例如在尿液中生长或附着于人输尿管组织后。 我们也有证据表明，除破坏菌毛组装外，杀菌毛剂对UPEC有其他影响。 使用微阵列，我们将阐明这些杀菌毛剂的作用，这样我们就可以了解所有的机制杀菌毛剂的行动。 这些研究将增加我们对UPEC皮利的杀菌作用的理解，并使我们能够进一步优化这些化合物在治疗UTI中的治疗用途。