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Principal Investigator: Morgan Rose Wilt Timm
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $34,926
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <A baumanni><A baumannii><A. baumanni><A. baumannii><A.baumannii><Acinetobacter baumanni><Acinetobacter baumannii><Address><Adherence><Adhesives><Alimentary Canal><Antibiotic Agents><Antibiotic Drugs><Antibiotic Therapy><Antibiotic Treatment><Antibiotics><Antimicrobial Resistance><Bacteria><Bacteria resistance><Bacteria resistant><Bacterial Adhesins><Bacterial resistant><Binding><Bladder><Bladder Transitional Cell Epithelium><Bladder Urinary System><Bladder Urothelium><Blood Coagulation Factor I><Blood Coagulation Factor One><Blood Factor One><Body Tissues><COVID-19><CV-19><Catalogs><Catheterization><Catheters><Cessation of life><Chronic><Clinical Treatment Moab><Coagulation Factor I><Coagulation Factor One><Communicable Diseases><Coronavirus Infectious Disease 2019><Data><Death><Deposit><Deposition><Development><Digestive Tract><Disease><Disorder><Distant><Dose><E faecalis><E. faecalis><Enterococcus><Enterococcus faecalis><Environment><Epithelial Cells><Epithelium><Factor I><Factor One><Fellowship><Female Health><Fibrinogen><Future><GI Tract><GI colonization><Gastrointestinal Tract><Gastrointestinal tract structure><Genes><Goals><History><Human><Immunity><Immunization><Immunize><Immunofluorescence><Immunofluorescence Immunologic><Immunology><In Vitro><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Infective cystitis><Inflammatory Response><Institution><Investigators><Ligands><Mediating><Mice><Mice Mammals><Microbial Biofilms><Microbiology><Miscellaneous Antibiotic><Modeling><Modern Man><Molecular Interaction><Monitor><Monoclonal Antibodies><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Murine><Mus><Nature><Pathogenesis><Pathogenicity Factors><Physicians><Pilum><Play><Prevention><Protein Subunits><Proteins><QOL><Quality of life><Recording of previous events><Recurrence><Recurrent><Research><Research Personnel><Researchers><Resistance><Resistance development><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistant development><Resistant to Multiple Drug><Resistant to multi-drug><Resistant to multidrug><Role><S faecalis><S. faecalis><Safety><Scientist><Source><Specificity><Streptococcus Group D><Streptococcus enterococcus group><Streptococcus faecalis><Surface><Testing><Therapeutic><Tissue Stains><Tissues><Training><UPEC><United States><Universities><Urethra><Urinary tract infection><Urinary tract infectious disease><Uropathogen><Uropathogenic E coli><Uropathogenic E. coli><Uropathogenic Escherichia coli><Vagina><Virulence Factors><Washington><Woman><Women's Health><Work><adhesin><alimentary tract><anti-microbial resistant><appendage><bacterial disease treatment><bacterial infectious disease treatment><bacterial resistance><biofilm><bladder infection><burden of disease><burden of illness><career><catalog><catheter associated UTI><catheter associated urinary tract infection><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><developing resistance><developmental><digestive canal><disease burden><experience><experiment><experimental research><experimental study><experiments><female genital tract><female genital tract infection><female reproductive tract><female reproductive tract infection><female treatment><gastrointestinal tract colonization><genital tract infection in women><global health><gut colonization><histories><improved><in vivo><indexing><infection in the female genital tract><infection in the female reproductive tract><infection recurrence><intestinal colonization><mAbs><medical college><medical schools><monoclonal Abs><mouse model><multi-drug resistant><multidrug resistant><murine model><mutant><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathogen><pilus><prevent><preventing><prophylactic><protective effect><recurrent infection><recurring infection><reproductive tract infection in women><resistance to Bacteria><resistance to Bacterial><resistance to anti-microbial><resistant><resistant to Bacteria><resistant to Bacterial><resistant to antimicrobial><school of medicine><sex><skills><social role><success><therapeutic target><treat females><treat women><treatment among females><treatment among women><treatment in females><treatment in women><urethral><urinary><urinary bladder><urinary infection><urinary tract catheter infection><women's genital tract><women's reproductive tract><women's treatment>