1 . Urinary tract infections (UTI) are extremely common world-wide, and can lead to serious 2 complications, including renal scarring and urosepsis. Standard-of-care treatments rely on antibiotics: empiric 3 treatment for uncomplicated UTI (uUTI), broad-spectrum for complicated UTI (cUTI), and long-term prophylaxis 4 for recurrent UTI (rUTI). This constant antibiotic exposure not only disrupts the gut microbiome but drives 5 antimicrobial resistance among uropathogenic Escherichia coli (UPEC) and Klebsiella pneumoniae (Kp), the 6 predominant causative agents of UTI. The global spread of multidrug-resistant uropathogens, such as those 7 caused by extended spectrum b-lactamase (ESBL)-producing and carbapenem-resistant Enterobacteriaceae 8 (CRE), has been designated by the CDC as "serious" and "urgent" public health threats, respectively. Therefore, 9 new strategies to combat multidrug resistance are desperately needed. One such approach is to target and 10 inhibit the function a key virulence factor of UPEC and Kp, the FimH adhesin. FimH is a surface-exposed, 11 mannose-binding protein that facilitates bacterial binding to the host urinary bladder epithelium, and its function 12 is essential for the establishment and persistence of a UTI. Using this anti-adhesive strategy, a small molecule 13 mannoside FimH antagonist was developed by Fimbrion and GlaxoSmithKline and is currently in Phase 1b 14 clinical trials for the treatment of uUTI. As a follow-up to this collaboration, we began exploring the next 15 generation of FimH antagonists that target the more difficult-to-treat cUTI, by additionally recruiting antibodies 16 from the host immune system. Known as FimH antagonist antibody recruiting molecules (FimH-ARMs), these 17 mannoside-based therapeutics have nanomolar affinity for the FimH target and our early protype FimH-ARM has 18 shown enhanced ability to reduce the severity of acute bladder infection in a mouse model of uUTI. We 19 hypothesize that in addition to antagonism of FimH function, FimH-ARMs will provide additional mechanisms of 20 action (MoAs) through engagement of the immune system and extended pharmacokinetics (PK), resulting in 21 superior efficacy over conventional mannosides in cUTI. The main goals of this proposal are: (1) to generate a 22 highly potent lead series of FimH-ARMs that will recruit naturally occurring human antibodies to uropathogenic 23 bacteria and (2) demonstrate in vivo efficacy in a model of cUTI. To accomplish these goals, we will (i) expand 24 the FimH-ARM library to identify potent lead compounds with optimized mouse PK profiles, and (ii) test the in 25 vivo efficacy of lead FimH-ARMs in a mouse cUTI model and (iii) Select our advanced lead FimH-ARM and 26 establish the spectrum of activity, MoA, and PK benchmarks for late lead optimization in Phase II. Success will 27 be defined as: identification of an advanced lead FimH-ARM, that shows in vivo efficacy superior to its parent 28 small molecule FimH antagonist and non-inferiority to a standard-of-care antibiotic and demonstrates additional 29 immune system MoAs beyond FimH antagonism. These studies will facilitate the early preclinical development 30 of a novel, antibiotic-sparing therapeutic, for preventing cUTI caused by FimH-expressing uropathogens.
Public Health Relevance Statement: PROJECT NARRATIVE Urinary tract infections and their complications are common and antibiotic usage for these conditions is a major driver of antimicrobial resistance, so alternative therapeutic strategies are needed. To meet this need, Fimbrion is proposing to develop a drug that recruits naturally occurring human antibodies to the pathogenic bacteria that cause urinary tract infections. This research program will begin the pre-clinical studies necessary to develop this drug as a narrow-spectrum, antimicrobial-sparing, antibody recruiting molecule therapy for the prevention of complicated urinary tract infections.
Project Terms: Adhesives; K pneumoniae; K. pneumoniae; Klebsiella pneumoniae; Antibiotic Agents; Antibiotic Drugs; Miscellaneous Antibiotic; Antibiotics; Antibodies; Clinical Treatment Moab; mAbs; monoclonal Abs; Monoclonal Antibodies; Bacteria; Biological Availability; Bioavailability; Physiologic Availability; Bladder; Bladder Urinary System; urinary bladder; Blood; Blood Reticuloendothelial System; Cells; Cell Body; Clinical Trials; comorbidity; co-morbid; co-morbidity; Drug Design; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Enterobacteriaceae; Coliform Bacilli; Enteric Bacteria; Enterobacteria; Goals; Half-Life; Health; Human; Modern Man; Immune system; In Vitro; Infection; Lead; Pb element; heavy metal Pb; heavy metal lead; Libraries; Long-Term Care; extended care; longterm care; Mannose; D-Mannose; Mannopyranose; Mannopyranoside; Mannosides; Mission; Mus; Mice; Mice Mammals; Murine; Parents; parent; Patients; Drug Kinetics; Pharmacokinetics; Proteins; Public Health; Recurrence; Recurrent; Research; Rhamnose; 6-deoxy-mannose; Deoxymannose; Risk; Testing; Urinary Catheterization; catheterized urine; Urinary tract infection; Urinary tract infectious disease; urinary infection; Urination; micturition; Urine; Mannose Binding Lectin; Mannan-Binding Lectin; Mannan-Binding Protein; Mannose-Binding Protein; Mannose-Specific Lectin; Generations; Microbial Biofilms; biofilm; Gram-Negative Bacterial Infections; Intensive Care; Catheters; Resistance to antibiotics; Resistant to antibiotics; antibiotic drug resistance; antibiotic resistant; Antibiotic Resistance; Mediating; Prophylaxis; Prophylactic treatment; Surface; Acute; Phase; Epithelium; pilus; Pilum; Multidrug Resistance; Multiple Drug Resistance; Multiple Drug Resistant; Resistance to Multi-drug; Resistance to Multidrug; Resistance to Multiple Drug; Resistant to Multiple Drug; Resistant to multi-drug; Resistant to multidrug; multi-drug resistant; multidrug resistant; Multi-Drug Resistance; adhesin; Bacterial Adhesins; Antibacterial Agents; anti-bacterial; antibacterial; Anti-Bacterial Agents; Collaborations; Case Fatality Rates; Therapeutic; programs; Immune; Immunes; Severities; Complex; Oral; subcutaneous; subdermal; Benchmarking; Best Practice Analysis; benchmark; success; urinary bladder epithelium; Infective cystitis; bladder infection; novel; Prevention; Modeling; Property; Pathogenicity Factors; Virulence Factors; Molecular Interaction; Binding; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; pharmaceutical; Pharmacologic Substance; Cellular Immune Function; immune function; preventing; prevent; small molecule; Dose; Antimicrobial Resistance; Antimicrobial resistant; Resistance to antimicrobial; anti-microbial resistance; anti-microbial resistant; resistance to anti-microbial; resistant to anti-microbial; resistant to antimicrobial; Affinity; Data; in vitro Assay; in vivo; Clinical Treatment; trial regimen; trial treatment; Invaded; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; follow-up; Active Follow-up; active followup; follow up; followed up; followup; urinary; Development; developmental; renal scarring; preclinical study; pre-clinical study; designing; design; Uropathogen; UPEC; Uropathogenic E coli; Uropathogenic Escherichia coli; Uropathogenic E. coli; Outcome; Prevention therapy; pathogen; bacteria pathogen; bacterial pathogen; pathogenic bacteria; innovate; innovative; innovation; Impairment; anti-microbial; antimicrobial; Implant; 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 therapy; novel therapeutics; murine model; mouse model; commercial application; prototype; combat; standard of care; lead series; Phase I Study; phase 1 study; carbapenem-resistant Enterobacteriaceae; GI microbiome; digestive tract microbiome; enteric microbiome; gastrointestinal microbiome; gut-associated microbiome; intestinal biome; intestinal microbiome; gut microbiome; Extended-spectrum beta-lactamase; Extended-spectrum ß-lactamase; nano-molar; nanomolar; clinical candidate; pre-clinical development; preclinical development; Immunize; recruit; healthcare settings; health care settings; lead optimization; Phase 1b Clinical Trial; Phase Ib Clinical Trial; antagonist; antagonism
