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

Washington University, Saint Louis MO

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Abstract

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.