Project Grant R44AI170297

A NEW CLASS OF BROAD-SPECTRUM ANTIBACTERIAL AGENTS TO TREAT MULTI-DRUG RESISTANT PATHOGENS - PROJECT SUMMARY CURZA IS DEVELOPING THE CZ-02 PLATFORM OF BROAD-SPECTRUM ANTIBIOTICS AS A NEW CLASS FOCUSING ON MULTIDRUG- RESISTANT (MDR) GRAM-NEGATIVE PATHOGENS THAT WILL ALSO BE EFFICACIOUS AGAINST GRAM-POSITIVE BACTERIA. CZ-02 ANTIBACTERIALS BIND TO A UNIQUE SITE ON THE BACTERIAL RIBOSOME THAT IS NOT TARGETED BY ANTIBIOTICS AVAILABLE CLINICALLY WHICH IS EXPECTED TO LIMIT CROSS-RESISTANCE TO OTHER ANTIBIOTICS. THE INITIATION AND SUBSEQUENT DEVELOPMENT OF THE CZ-02 PROGRAM REPRESENTS A STRONG EXAMPLE FOR REVISITING THE USE OF NATURAL PRODUCTS IN DRUG DISCOVERY WHICH HAS FALLEN OUT OF FAVOR IN PHARMA. CZ-02S WERE INSPIRED BY THE NATURAL PRODUCT AMICETIN WHICH SELECTIVELY INHIBITS BACTERIAL PROTEIN SYNTHESIS BUT SUFFERS FROM LIMITED ANTIBACTERIAL ACTIVITY AND POOR DRUG-LIKE PROPERTIES. CAREFUL ENGINEERING OF THE NATURAL PRODUCT HAS PRODUCED CZ-02S WITH EXQUISITE SELECTIVITY FOR BACTERIAL PROTEIN SYNTHESIS, POTENT ANTIBACTERIAL ACTIVITY AND EXCELLENT DRUG-LIKE PROPERTIES THAT HAVE DEMONSTRATED EFFICACY AGAINST MDR PATHOGENS IN MULTIPLE ANIMAL MODELS OF INFECTION WHILE SPARING MAMMALIAN CELLS FROM CYTOTOXICITY. THE GOAL OF THIS DIRECT-TO-PHASE II PROJECT IS TO DEVELOP A NEW ANTIBACTERIAL DRUG CANDIDATE THAT COVERS GRAM- NEGATIVE PATHOGENS FOUND AMONG ENTEROBACTERALES AND THE NON-FERMENTERS ACINETOBACTER BAUMANNI AND PSEUDOMONAS AERUGINOSA AS WELL AS GRAM-POSITIVE PATHOGENS. THE INITIAL CLINICAL INDICATION WILL BE FOR TREATING URINARY TRACT INFECTIONS (UTIS), WITH OTHER INDICATIONS TO FOLLOW (E.G. COMPLICATED INTRA-ABDOMINAL INFECTIONS, PNEUMONIA, BACTEREMIA). AT THE CONCLUSION OF THIS PHASE II SBIR WILL BE A PRE-CLINICAL DEVELOPMENT CANDIDATE THAT IS POTENT WITH BROAD SPECTRUM ACTIVITY THAT WILL BE READY FOR CHEMISTRY, MANUFACTURING AND CONTROLS (CMC) AND TOXICOLOGY/SAFETY PHARMACOLOGY UNDER GOOD LABORATORY PRACTICES (GLP). ADVANCEMENT OF THIS ANTIBACTERIAL LEAD SERIES WILL BE ACCOMPLISHED BY THE FOLLOWING AIMS. AIM 1 WILL EXPAND THE SPECTRUM OF ACTIVITY FOR ADVANCED LEADS THAT HAVE SHOWN EFFICACY IN UTI ANIMAL MODELS WITH MDR GRAM-NEGATIVE PATHOGENS. CURZA'S PROPRIETARY MODEL FOR PRODUCING POTENT AND SELECTIVE INHIBITORS OF BACTERIAL P-SITE PROTEIN SYNTHESIS, IN COMBINATION WITH A BATTERY OF BIOLOGICAL/BIOCHEMICAL ACTIVITY ASSAYS (BIOCHEMICAL, MICROBIOLOGICAL, IN VITRO ADME-TOX), WILL BE USED FOR CHEMISTRY EFFORTS TO ENSURE COMPOUNDS RETAIN ACTIVITY WHILE EXPANDING THE SPECTRUM OF ADDRESSABLE PATHOGENS TO INCLUDE A. BAUMANNII AND P. AERUGINOSA. AIM 2 WILL DEFINE PHARMACOKINETICS (PK) WHILE IDENTIFYING THE MAXIMUM TOLERATED DOSE AND CONFIRMING EFFICACY BY TESTING IN THIGH INFECTION MODELS TO SELECT CZ-02S FOR EVALUATION IN UTI MODELS. A LEAD AND BACKUP DRUG CANDIDATE WILL BE SELECTED IN AIM 3 BY EVALUATION IN UTI MODELS OF ANTIBIOTIC-RESISTANT BACTERIA FOLLOWED BY NON-GLP TOXICOLOGY IN RATS TO NOMINATE A LEAD AND BACKUP. AIM 4 WILL SCALE-UP PRODUCTION (NON-GLP) TO SUPPORT IN VIVO STUDIES WHILE AIM 5 WILL ESTABLISH THE OPTIMAL DOSING STRATEGY FROM PK/PHARMACODYNAMIC (PD) STUDIES.