Novel therapeutics for treatment of catheter-associated UTI and depletion of the vaginal reservoir

项目摘要/摘要

PROJECT SUMMARY / ABSTRACT Antimicrobial resistance (AMR) contributes to an estimated 5 million deaths worldwide each year and is directly responsible for over 1.2 million deaths. In the not-to-distant future, we may face a reality where infections resistant to all existing antibiotics are commonplace. Therefore, addressing antimicrobial resistance by developing antibiotic-sparing therapeutics is an urgent global health concern. Urinary tract infections (UTI) drive over 15% of all antibiotic prescriptions and directly contribute to the development of AMR bacteria. One potential antibiotic-sparing therapeutic for UTIs is monoclonal antibodies (mAbs), which have been successfully deployed for decades and have a strong history of safety and efficacy. The objective of this proposal is to develop mAbs to two types of UTIs that greatly contribute to global disease burden. The overall hypothesis is that mAbs to bacterial pilus adhesin proteins will block adhesin-ligand interactions and thus prevent bacterial adherence to host tissues. In Aim 1, mAbs will be explored as a treatment for catheter- associated UTI (CAUTI) caused by two pathogens that are frequently multi-drug resistant: Enterococcus faecalis and Acinetobacter baumannii. These bacteria cause CAUTI by using sticky adhesins to bind to fibrinogen deposited on the surface of urinary catheters. mAbs will block this interaction to prevent catheter colonization. In Aim 2, mAbs will be tested for their ability to block bacterial interaction with host tissue. Uropathogenic Escheriscia coli (UPEC) frequently causes highly recurrent UTI (rUTI) in part by establishing reservoirs in the gastrointestinal tract and vagina that serve as a source for UPEC’s continuous reintroduction into the bladder lumen. While the adhesins responsible for gut colonization have been characterized, the adhesin responsible for vaginal colonization is unknown. Based on existing data suggesting a role for the UPEC S pilus in the vagina, the contribution of this pilus to vaginal colonization will first be elucidated. mAbs will then be generated to the S pilus adhesin and tested for their ability to deplete UPEC from the vagina. The long-term goal of the proposed research is to generate mAbs that can treat human urinary tract infections. During the fellowship, the applicant will develop important skills for becoming an independent investigator of infectious diseases. The sponsor of this work, Dr. Scott Hultgren, has vast experience studying urinary tract infection pathogenesis and treatment, and the institutional environment provides supportive, collaborative experts in microbiology and immunology. Washington University School of Medicine has a long history of helping physician-scientists build successful careers. The proposed training plan will facilitate the applicant’s transition into becoming an independent physician-scientist, using research to improve women’s health.