EXPRESSION AND IRON-INDEPENDENT FUNCTIONS OF SIDEROPHORES IN URINARY TRACT INFECT

描述(申请人提供)：尿路感染(UTI)是最常见的人类传染病之一。虽然大多数尿路感染是自我限制的，但由尿路致病性大肠杆菌(UPEC)引起的尿路感染有可能发展到肾脏和血液感染，这促使大量抗生素的使用。随着人口老龄化和抗生素耐药性的急剧增加，有必要更好地了解和管理这种疾病。确定UPEC致病特征的努力一直指向铁载体的重要作用，铁载体是一个化学多样性的小分子家族，其定义是它们结合铁的能力供微生物使用。大多数尿路病原体携带两种、三种甚至四种不同的铁载体类型的基因组，尽管它们在铁摄取方面存在功能冗余。我们推测，UPEC表达的额外铁载体在铁获取之外执行独特的功能，并代表新的治疗和诊断靶点。我们开发了新的基于质谱学的分析，以确定临床上最关注的UPEC分离株的特征，并通过检测它们与宿主因子的原子水平相互作用来确定相关的铁载体功能。使用这种方法，我们最近发现了毒力相关的UPEC铁载体和宿主来源的铜离子之间的一种意想不到的和病原学意义上的相互作用。由于UPEC菌株不仅与尿液相互作用，而且与宿主细胞和组织相互作用，我们将研究它们的铁载体如何在这两种环境中发挥作用。在这项研究的结论中，我们将对铁载体在尿路感染发病机制中的作用有了新的见解，并确定了这种常见和有问题的疾病的新诊断和治疗策略。

DESCRIPTION (provided by applicant): Urinary tract infections (UTI) are one of the most common human infectious diseases. Although most UTIs are self-limited, the potential for those caused by uropathogenic E.coli (UPEC) to progress to kidney and bloodstream infections motivates significant antibiotic use. As an aging population converges with a dramatic increase in antibiotic resistance, it will be necessary to better understand and manage this disease. Efforts to identify UPEC's disease-causing features consistently point to an important role for siderophores, a chemically diverse family of small molecules defined by their ability to bind ferri iron for microbial use. Most uropathogens carry gene sets for two, three, or even four distinct siderophore types despite their functional redundancy for iron uptake. We hypothesize that the additional siderophores expressed by UPEC execute distinctive functions beyond iron acquisition and represent new therapeutic and diagnostic targets. We have developed new mass spectrometry-based analyses to characterize UPEC isolates of greatest clinical concern and to identify associated siderophore functions by detecting their atomic-level interactions with host factors. Using this approach we recently identified an unexpected and pathogenically significant interaction between a virulence-associated UPEC siderophore and host-derived copper ions. Because UPEC strains interact not only with urine but also with host cells and tissues, we will examine how their siderophores function in both of these environments. At this study's conclusion we will have gained new insights into the role of siderophores in UTI pathogenesis and identified new diagnostic and therapeutic strategies for this common and problematic illness.