Combating Multidrug-Resistant Urinary Tract Infections in Spinal Cord Injury Patients
Abstract
Every year, approximately 12,000 individuals are diagnosed with spinal cord injury (SCI), many of which are active military personnel or Veterans. These patients often require the use of catheters, which increases the likelihood of developing chronic and recurrent urinary tract infections (UTIs). Patients who suffer from more than four UTIs per year have dramatic decreases in their quality of life. Moreover, patients who experience multiple UTIs per year – as is common among SCI patients – risk developing difficult-to-treat drug-resistant infections. However, a subset of patients appears protected from these severe, recurrent infections. This work will (1) determine how a patient’s own bladder-resident microbes, the urinary microbiota, can protect them from infection, and (2) develop new treatments for the severe, drug-resistant UTIs that plague SCI patients. While mobility is the major concern of newly injured SCI patients, bladder and bowel management are long- term concerns and one of the greatest drivers of quality-of-life in these patients. When patients report recurrent infections – defined as four or more UTIs in 1 year – reported quality-of-life plummets. Unfortunately, since recurrent infections are often caused by the same bacterial populations as prior infections, they have been exposed to multiple antibiotics and are therefore more likely to be antibiotic resistant, including multidrug resistant (MDR), or super bugs. In severe cases, these superbugs can escape from the urinary tract into the kidneys or bloodstream, causing sepsis and death. The three aims in this research proposal are intertwined to ensure a global attack on this problem. Aim 1 will determine the differences in the types of bacteria that colonize the urinary tract of patients who experience multiple symptomatic recurrent infections versus those who do not. This will allow for identification of specific types of bacteria and bacterial factors that might protect against symptomatic UTIs. This information will then be exploited to help develop probiotic bacterial strains that can be used to treat and prevent UTI. This work will also identify new antimicrobial small molecules that can be developed into antibiotic drugs. Aim 2 will use high-throughput screening and analysis methods to identify drugs that act synergistically with antibiotics commonly used to treat UTIs. These synergistic interactions dramatically increase the efficacy of the drug combination compared to each individual drug but have historically been difficult to identify. Our analysis method overcomes this bottleneck. Moreover, in this initial stage, we focus on synergistic pairs consisting of drugs already approved for other indications, so that they can rapidly be moved into clinical use without expensive and time-consuming trials. Finally, Aim 3 develops antibody-drug conjugates (ADCs) to precisely target infecting bacteria and specifically deliver their payload, reducing systemic side effects. This will involve engineering linkers between drugs and antibodies that can only be cleaved by pathogenic bacteria, releasing drugs where they are most needed. Long-term, these antibodies will incorporate drugs discovered in Aims 1 and 2 . By taking a holistic approach to studying UTIs in SCI patients, our team seeks to identify new treatment options to offer hope to these patients that their repeated struggles with these infections can be alleviated and develop preventative tools to aid newly diagnosed patients in avoiding these recurrent infections altogether, which will dramatically improve their quality of life.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210800
Entities
People
- Matthew Mulvey
Organizations
- United States Army
- University of Utah