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.
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.
|Robinson, Anne E; Henderson, Jeffrey P; Henzler-Wildman, Katherine A (2018) A mass spectrometry based transport assay for studying EmrE transport of unlabeled substrates. Anal Biochem 549:130-135|
|Robinson, Anne E; Lowe, Jessica E; Koh, Eun-Ik et al. (2018) Uropathogenic enterobacteria use the yersiniabactin metallophore system to acquire nickel. J Biol Chem 293:14953-14961|
|Robinson, Anne E; Heffernan, James R; Henderson, Jeffrey P (2018) The iron hand of uropathogenic Escherichia coli: the role of transition metal control in virulence. Future Microbiol 13:745-756|
|Ohlemacher, Shannon I; Giblin, Daryl E; d'Avignon, D André et al. (2017) Enterobacteria secrete an inhibitor of Pseudomonas virulence during clinical bacteriuria. J Clin Invest 127:4018-4030|
|Koh, Eun-Ik; Robinson, Anne E; Bandara, Nilantha et al. (2017) Copper import in Escherichia coli by the yersiniabactin metallophore system. Nat Chem Biol 13:1016-1021|
|Shields-Cutler, Robin R; Crowley, Jan R; Miller, Connelly D et al. (2016) Human Metabolome-derived Cofactors Are Required for the Antibacterial Activity of Siderocalin in Urine. J Biol Chem 291:25901-25910|
|Trevino, Sergio E; Henderson, Jeffrey P; Wu, Jiami et al. (2016) Prevalence of Asymptomatic Bacteriuria in Hospitalized Patients. Infect Control Hosp Epidemiol 37:749-51|
|Koh, Eun-Ik; Hung, Chia S; Henderson, Jeffrey P (2016) The Yersiniabactin-Associated ATP Binding Cassette Proteins YbtP and YbtQ Enhance Escherichia coli Fitness during High-Titer Cystitis. Infect Immun 84:1312-1319|
|Shields-Cutler, Robin R; Crowley, Jan R; Hung, Chia S et al. (2015) Human Urinary Composition Controls Antibacterial Activity of Siderocalin. J Biol Chem 290:15949-60|
|Koh, Eun-Ik; Hung, Chia S; Parker, Kaveri S et al. (2015) Metal selectivity by the virulence-associated yersiniabactin metallophore system. Metallomics 7:1011-22|
Showing the most recent 10 out of 16 publications