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.

Public Health Relevance

Bacteria that cause bladder infection and can progress to kidney or blood infection are increasingly antibiotic resistant. Identifying the virulence-associatd molecules these bacteria make during UTI and understanding how they help cause infections will improve future patient care by improving diagnoses and treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK099534-01A1
Application #
8760744
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Kirkali, Ziya
Project Start
2014-07-01
Project End
2019-04-30
Budget Start
2014-07-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Koh, Eun-Ik; Henderson, Jeffrey P (2015) Microbial Copper-binding Siderophores at the Host-Pathogen Interface. J Biol Chem 290:18967-74

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