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

描述（由申请人提供）：尿路感染（UTI）是人类最常见的传染病之一。虽然大多数UTI是自限性的，但由尿路致病性大肠杆菌（UPEC）引起的UTI发展为肾脏和血流感染的可能性促使人们大量使用抗生素。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。努力确定UPEC的致病特征一致指向铁载体的重要作用，铁载体是一个化学上多样化的小分子家族，其定义为结合亚铁离子以供微生物使用的能力。大多数尿路病原体携带两个，三个，甚至四个不同的铁载体类型的基因集，尽管他们的功能冗余铁摄取。我们假设UPEC表达的额外铁载体执行铁获取之外的独特功能，并代表新的治疗和诊断靶点。我们已经开发了新的基于质谱的分析，以表征最大的临床关注的UPEC分离株，并通过检测它们与宿主因子的原子级相互作用来识别相关的铁载体功能。使用这种方法，我们最近确定了一个意想不到的和致病性显着的毒力相关的UPEC铁载体和宿主衍生的铜离子之间的相互作用。由于UPEC菌株不仅与尿液相互作用，还与宿主细胞和组织相互作用，因此我们将研究它们的铁载体在这两种环境中的功能。在这项研究的结论，我们将获得新的见解铁载体在UTI发病机制中的作用，并确定了新的诊断和治疗策略，这种常见的和有问题的疾病。

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.