Baylor College of Medicine, Houston,TX, USA
Urinary tract infections (UTI) are a major medical burden in the United States. Seven million UTIs occur each year, representing the most common cause of antibiotic prescriptions in the out-patient setting. A significant portion of affected individuals will have recurrent UTI (rUTI), defined as three UTIs in a calendar year, requiring additional antibiotic treatment. UTIs are becoming more difficult to treat as antibiotic resistance emerges as an increasing issue among urinary pathogens including with uropathogenic E. coli (UPEC), the most common pathogen associated with UTI. Therefore, alternative treatment strategies are urgently needed. Bacteriophages (phage), viruses that selectively infect bacteria, are an appealing targeted therapy for many bacterial pathogens, but their efficacy in the treatment of UTI is not well-defined. To date, previous literature on phage-mediated killing of E. coli has focused on interactions in rich bacteriologic media or in human blood. However, these media conditions fail to accurately reflect the nutrient composition, pH, osmolarity, and host proteins present in the urinary tract environment. Our objective is to characterize interactions between phage and bacteria in the urinary tract environment with the goal of maximizing the bacteriophage therapeutic potential. To this end, we screened a library of environmentally-isolated E. coli phages for killing activity towards a variety of UPEC isolates, varying the culture media (LB or human pooled urine) and the concentration of phage used. We measured phage-mediated killing using a plate reader measuring the optical density over an 18-hour timeframe. Our results demonstrate that, although bacterial killing occurs in both culture conditions and varies across phage/UPEC strain combinations, urine is broadly inhibitory towards phage-mediated killing of UPEC. Additionally, we observed emergence of phage-resistant UPEC in both media environments. Ongoing work seeks to characterize the genetic basis for phage resistance in urine, and to assess phage killing efficacy and bacterial resistance in vivo using murine UPEC UTI models. In the future, we plan to develop phage-antibiotic cocktails that restrict development of bacterial resistance, with the goal of developing phage therapies for treating and preventing recurrent UTIs.