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: 8644113
• 负责人: SARAH Elizabeth GREENE
• 金额: $ 2.89万
• 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/8644113
• 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%的女性在其一生中，其中许多女性经历复发性感染。80%的社区获得性尿路感染和50%的医院感染是由尿路致病性大肠杆菌（UPEC）引起的。UPEC中抗生素耐药率的增加需要开发新的治疗方法来治疗这些感染。UPEC利用黏附的1型细胞外细胞器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