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Principal Investigator: SCOTT J. HULTGREN
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $366,301
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT:
The climate surrounding COVID-19 has dramatically reminded us of the dire consequences of being
unprepared for health crises. One looming health crisis is the surge of antibiotic-resistant bacterial infections
that are no longer sensitive to our life saving antibiotic arsenal. Thus, this project is leveraged to translate basic
science into antibiotic-sparing medicines for one of the most common bacterial infections in the United States,
urinary tract infections (UTIs), as well as the most common hospital-acquired infection, catheter-associated
UTIs (CAUTIs). The strategy is to develop therapeutics that work equally well against carbapenem-resistant
Enterobacteriaceae (CRE) and extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae,
including the cause of over 80% of community-acquired UTIs, uropathogenic Escherichia coli (UPEC). CAUTIs
pose a significant challenge for healthcare globally. While UPEC causes 50% of CAUTI, other pathogens,
including ESBL and CRE Klebsiella, multidrug resistant (MDR) Acinetobacter and Gram-positive Enterococcus
including vancomycin resistant Enterococcus (VRE), cause a significant proportion of CAUTIs. These MDR
pathogens express adhesive factors required for colonization and infection in different host habitats involved in
acute and chronic/recurrent UTIs as well as in CAUTIs. Small molecules and monoclonal antibodies (mAbs)
will be developed that will treat and prevent disease by blocking these critical host-pathogen interactions. By
acting extracellularly, these antibiotic-sparing therapeutics will be recalcitrant to intracellular mechanisms of
resistance and avoid a common obstacle of cell permeability in drug discovery of small molecules. UPEC,
Klebsiella and Acinetobacter express chaperone usher pathway (CUP) pili tipped with adhesins: i) FimH,
FmlH, YehD, UclD (UPEC); ii) FimH (Klebsiella) and iii) CupD (Acinetobacter). These adhesins are critical for
colonization of the bladder (FimH), inflamed bladder and kidney (FmlH), gut (FimH, UclD and YehD) and
catheters (FimH and CupD). Further, Enterococcus faecalis express EbpA-tipped sortase-assembled pili,
which are critical in CAUTI. Glycomimetics have shown great promise in neutralizing CUP adhesins in vivo to
treat disease. For example, mannosides which neutralize FimH function, are potent therapeutics for treating
and preventing UTI, since FimH is required by UPEC to colonize the bladder. Validating the work in this
proposal, a mannoside has been selected, in collaboration with GSK, to proceed into phase 1a/ab clinical trials
in humans. Also, a FimH vaccine has completed Phase 1a/1b clinical trials. The use of mAbs has
revolutionized treatments for cancer, inflammatory, and neuronal disorders. Therapeutic mAbs have not yet
been fully harnessed for treating infectious diseases, perhaps due to the historic success of antibiotics. In this
project, we will develop therapeutic mAb designed to prevent critical host-pathogen interactions by neutralizing
the adhesins described above. The combined strategies have the potential to produce transformative
antibiotic-sparing therapeutics that work equally well against and antibiotic-sensitive and resistant infections.
Terms: <Acinetobacter><Acute><Adhesives><Affinity><Alimentary Canal><Antibiotic Agents><Antibiotic Drugs><Antibiotic Resistance><Antibiotics><Antibodies><Antibody Therapy><Bacteria><Bacterial Adhesins><Bacterial Antibiotic Resistance><Bacterial Infections><Basic Research><Basic Science><Binding><Bioavailability><Biological Availability><Bladder><Bladder Urinary System><Blood Coagulation Factor I><Blood Coagulation Factor One><Blood Factor One><Body Tissues><COVID-19><CV-19><Calymmatobacterium><Cancer Treatment><Catheters><Cell Body><Cell Wall><Cells><Chaperone><Chronic><Chronic Cystitis><Climate><Clinical Treatment><Clinical Treatment Moab><Clinical Trials><Coagulation Factor I><Coagulation Factor One><Coliform Bacilli><Collaborations><Communicable Diseases><Coronavirus Infectious Disease 2019><D-Galactose><D-Mannose><Development><Digestive Tract><Disease><Disorder><Donovania><E faecalis><E. faecalis><Enteric Bacteria><Enterobacteria><Enterobacteriaceae><Enterococcus><Enterococcus faecalis><Extended-spectrum beta-lactamase><Extended-spectrum β-lactamase><Factor I><Factor One><Fibrinogen><Funding><GI Tract><GI colonization><Galactopyranose><Galactopyranoside><Galactose><Gastrointestinal Tract><Gastrointestinal tract structure><Gram-Negative Bacteria><Habitats><Health><Healthcare><Hospital Infections><Hospital acquired infection><Human><Implantable Catheters><In Vitro><In-Dwelling Catheters><Indwelling Catheter><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammatory><Ingestion><Invaded><K pneumoniae><K. pneumoniae><Kidney><Kidney Urinary System><Klebsiella><Klebsiella pneumoniae><Knowledge><Life><Ligands><MAb Therapeutics><MDR Acinetobacter><MDR organism><MDR pathogen><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Mannopyranose><Mannopyranoside><Mannose><Mannosides><Medicine><Meteorological Climate><Microbial Biofilms><Miscellaneous Antibiotic><Modeling><Modern Man><Molecular Chaperones><Molecular Interaction><Monoclonal Antibodies><Multi-drug resistant Acinetobacter><Multidrug-resistant Acinetobacter><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Nosocomial Infections><Oral><Pathogenicity><Pathway interactions><Pectins><Permeability><Phase><Phase 1a/1b Clinical trial><Phase Ia/Ib Clinical Trial><Physiologic Availability><Pilum><Plants><Pre-Clinical Model><Preclinical Models><Privatization><Receptor Protein><Recurrence><Recurrent><Research Resources><Resistance><Resistance profile><Resistance to antibiotics><Resistant profile><Resistant to antibiotics><Resources><S faecalis><S. faecalis><Streptococcus Group D><Streptococcus enterococcus group><Streptococcus faecalis><Structure-Activity Relationship><Surface><Testing><Therapeutic><Therapeutic Monoclonal Antibodies><Tissues><Translating><UPEC><United States><Urinary tract infection><Urinary tract infectious disease><Uropathogen><Uropathogenic E coli><Uropathogenic E. coli><Uropathogenic Escherichia coli><Vaccines><Vancomycin Resistance><Vancomycin resistant enterococcus><Vancomycin-resistant enterococci><Venous Reservoirs><Work><adhesin><alimentary tract><antagonism><antagonist><anti-cancer therapy><antibiotic drug resistance><antibiotic resistant><antibiotic resistant bacteria><antibiotic resistant infections><antibiotic resistant pathogen><antibody based therapies><antibody treatment><antibody-based therapeutics><antibody-based treatment><bacteria infection><bacterial antibiotic resistant><bacterial community><bacterial disease><bacterial resistance to antibiotic><biofilm><cancer therapy><cancer-directed therapy><candidate identification><carbapenem resistance in Enterobacteriaceae><carbapenem-resistant Enterobacteriaceae><catheter associated UTI><catheter associated urinary tract infection><chemical structure function><climatic><combat><community-acquired UTI><community-acquired urinary tract infection><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><design><designing><developmental><diabetic><digestive canal><drug discovery><drug resistant pathogen><experiment><experimental research><experimental study><experiments><extracellular><gastrointestinal><gastrointestinal tract colonization><global health><glycomimetics><gut colonization><health care><host colonization><implant coating><implantation><in vivo><ingest><innovate><innovation><innovative><institutional infection><intestinal colonization><life span><lifespan><mAbs><methoxy pectin><methoxylpectin><methoxypectin><mimetics><monoclonal Abs><monoclonal antibody drugs><mouse model><multi-drug resistant organism><multi-drug resistant pathogen><multidrug resistant organism><multidrug resistant pathogen><multiple drug resistant organism><multiple drug resistant pathogen><murine model><neuronal><pathogen><pathway><pectinic acid><pilus><pressure><prevent><preventing><programs><receptor><renal><residence><residential building><residential site><resistance mechanism><resistance to vancomycin><resistant><resistant mechanism><resistant to vancomycin><small molecule><sortase><srtA gene product><structure function relationship><success><therapeutic mAbs><tissue wound><trial regimen><trial treatment><urgent and serious threat><urgent or serious threat><urinary bladder><urinary infection><urinary tract catheter infection><vancomycin resistance enterococci><vancomycin resistance in enterococci><vancomycin resistant><wound><wounding><wounds>