Project Grant R43AI174482

FIMH-TARGETING ANTIBODY-RECRUITING MOLECULES AS NOVEL DRUGS FOR PREVENTING COMPLICATED URINARY TRACT INFECTIONS - 1 ABSTRACT. 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.