Optimizing anti-virulence compounds for the treatment of UTIs

描述(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%的院内获得性尿路感染是由尿路致病性大肠埃希菌(UPEC)引起的。UPEC对抗生素的耐药率不断上升，有必要开发新的治疗方法来治疗这些感染。UPEC使用粘附性细胞外细胞器1型菌毛与膀胱上皮上的甘露糖结合，允许细菌附着和入侵宿主细胞并建立感染。除了类型之外 1菌毛，UPEC编码许多同源类型的菌毛，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的细节，我们能够开发出合理设计来破坏菌毛组装的小分子。这些被称为杀菌剂的抗毒力化合物为尿路感染的治疗提供了一种新的方法，因为阻止菌毛组装或功能应该降低UPEC或其他编码同源菌毛的革兰氏阴性病原体的毒力。因此，我们建议研究杀菌剂在UPEC菌株UTI89以及其他泌尿系统病原体中破坏所有同源菌毛组装的有效性。由于这些菌毛通常是协同调节的，我们还将检测杀菌剂对这些菌毛表达的影响。此外，由于菌毛的表达受到环境信号的影响，我们将评估这些菌毛的表达以及杀菌剂在类似宿主的环境中的功能，例如在尿液中生长或附着在人体输尿管组织后。我们也有证据表明，杀菌剂除了破坏菌毛组装外，还对UPEC有其他影响。利用基因芯片，我们将阐明这些杀菌剂的作用，以便我们能够理解杀菌剂的所有作用机制。这些研究将增加我们对杀菌剂对UPEC菌毛影响的了解，并使我们能够进一步优化这些化合物用于治疗尿路感染的治疗用途。

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.