Over 15 million women suffer from urinary tract infections (UTI) annually in the U.S., ~85% of which are caused by uropathogenic Escherichia coli (UPEC). 20-40% of patients suffer from multiple and/or chronic recurrences and increasingly are left with few treatment options other than costly long-term antibiotic prophylaxis Indiscriminate use of antibiotics is leading to increased resistance to first-line empiric therapie such as trimethoprim-sulfamethoxazole and the undesirable use of fluoroquinolones for empiric treatment of UTI. Catheter-associated UTI (CAUTI) further exacerbates this problem. Consequently, multi-drug resistance is rising rapidly. Thus, there is a critical need for new therapeutics to better treat and prevent chronic recurrences. There are two bladder associated niches for UPEC during acute UTI: the bladder tissue and the luminal space/urine. FimH, the type 1 pilus adhesin mediates UPEC colonization and invasion of human and murine bladder epithelial cells (BECs). Murine models indicate that after invasion, UPEC can subvert innate expulsion mechanisms and escape into the cytoplasm where rapid bacterial replication results in the formation of intracellular bacterial communities (IBC) comprised of 104-105 bacteria. IBCs are transient and upon IBC maturation bacteria disperse from the biomass, filament, and spread to neighboring BECs, re-initiating the IBC cycle. This cycle potentiates the establishment of infection allowing the expansion of the bacterial population in a sequestered habitat protected from host immune and antibiotic clearance. Bacterial colonization of BECs, IBC formation, filamentation and biofilm formation on urinary catheters (also seen in mouse models) are all processes seen in human disease. Further, the fimH gene is under positive selection in UPEC clinical isolates consistent with its role in UTI. Murine models and human clinical studies show roles for the same specific cytokines and TLR4 signaling in UTI. In humans, UTI ranges from asymptomatic bacteriuria to acute self- limiting infection to chronic/recurrent UTI. Murine models mimic these disease outcomes and reveal that the nature of host response dictates whether a UTI resolves or develops into long-lasting chronic/recurrent UTI. This grant proposal will use a panel of virulent clinical isolates including a multi-drug resistant strain that has spread globall, to focus on a direct experimental investigation of common but complex clinical problems associated with more severe UTI and/or recurrence.
Aim 1 investigates mechanisms by which superinfection of UPEC leads to the development of chronic/recurrent infection.
Aim 2 investigates catheterization, which may alter the pathogenesis and may trigger the recurrence of infection in patients with a history of UTI.
Aim 3 investigates the efficacy of potent small molecular weight compounds called mannosides, which block FimH function, to treat and prevent UTI in the context of these complicating factors. The proposed experiments will elucidate how sequential infection and catheterization affect the course of UTI and aid in better clinical management and the development of new therapeutics for combating this prevalent infection.

Public Health Relevance

In this proposal we seek to investigate the effects of uropathogenic Escherichia coli (UPEC) superinfection and catheterization of the urinary tract on predisposing to recurrences or more severe chronic cystitis. We also test the efficacy of novel mannoside compounds for oral treatment of UTI caused by virulent and multi-drug resistant strains that have spread globally. Understanding the effect of these common complications will give insight into how urinary tract infection occurs and progresses in human patients and is necessary to develop effective therapies to combat a rise in antibiotic resistant bacteria.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Program Officer
Mullins, Christopher V
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Flores-Mireles, Ana L; Walker, Jennifer N; Bauman, Tyler M et al. (2016) Fibrinogen Release and Deposition on Urinary Catheters Placed during Urological Procedures. J Urol 196:416-21
Jarvis, Cassie; Han, Zhenfu; Kalas, Vasilios et al. (2016) Antivirulence Isoquinolone Mannosides: Optimization of the Biaryl Aglycone for FimH Lectin Binding Affinity and Efficacy in the Treatment of Chronic UTI. ChemMedChem 11:367-73
Flores-Mireles, Ana L; Walker, Jennifer N; Potretzke, Aaron et al. (2016) Antibody-Based Therapy for Enterococcal Catheter-Associated Urinary Tract Infections. MBio 7:
Conover, Matt S; Ruer, Ségolène; Taganna, Joemar et al. (2016) Inflammation-Induced Adhesin-Receptor Interaction Provides a Fitness Advantage to Uropathogenic E. coli during Chronic Infection. Cell Host Microbe 20:482-492
Conover, Matt S; Hadjifrangiskou, Maria; Palermo, Joseph J et al. (2016) Metabolic Requirements of Escherichia coli in Intracellular Bacterial Communities during Urinary Tract Infection Pathogenesis. MBio 7:e00104-16
O'Brien, Valerie P; Hannan, Thomas J; Nielsen, Hailyn V et al. (2016) Drug and Vaccine Development for the Treatment and Prevention of Urinary Tract Infections. Microbiol Spectr 4:
Spaulding, Caitlin N; Hultgren, Scott J (2016) Adhesive Pili in UTI Pathogenesis and Drug Development. Pathogens 5:
Ozer, Ahmet; Altuntas, Cengiz Z; Izgi, Kenan et al. (2015) Advanced glycation end products facilitate bacterial adherence in urinary tract infection in diabetic mice. Pathog Dis 73:
O'Brien, Valerie P; Hannan, Thomas J; Schaeffer, Anthony J et al. (2015) Are you experienced? Understanding bladder innate immunity in the context of recurrent urinary tract infection. Curr Opin Infect Dis 28:97-105
Conover, Matt S; Flores-Mireles, Ana L; Hibbing, Michael E et al. (2015) Establishment and Characterization of UTI and CAUTI in a Mouse Model. J Vis Exp :e52892

Showing the most recent 10 out of 111 publications