Project Grant R43AI172559

THIAZOLINO-PYRIDONE COMPOUNDS AS NOVEL DRUGS FOR TUBERCULOSIS - PROJECT SUMMARY/ABSTRACT TUBERCULOSIS (TB), CAUSED BY INFECTION WITH THE BACTERIUM MYCOBACTERIUM TUBERCULOSIS (MTB), IS A LEADING CAUSE OF MORTALITY DUE TO INFECTION, GLOBALLY. IN 2020, 10 MILLION PEOPLE WERE NEWLY DIAGNOSED WITH TB AND 1.5 MILLION PEOPLE DIED FROM THE DISEASE. AS EFFORTS TO TREAT TB EXPAND, THE PREVALENCE OF INFECTIONS CAUSED BY DRUG-RESISTANT MTB STRAINS (DR-TB) THAT ARE RESISTANT TO ONE OR MORE FRONTLINE STANDARD OF CARE (SOC) ANTIBIOTICS IS INCREASING, IN PART DUE TO THE LONG DURATION (6 MONTHS) OF COMBINATION THERAPY (4 ANTIBIOTICS) FOR DRUG-SENSITIVE TB (DS-TB), WHICH LEADS TO POOR PATIENT ADHERENCE. TREATMENT FOR DR-TB IS EVEN LONGER, RANGING FROM 6-24 MONTHS TYPICALLY, WITH 3, 4 OR MORE ANTIBIOTICS TAKEN IN COMBINATION. WHILE THE LAST DECADE HAS SEEN A TB DRUG DEVELOPMENT "RENAISSANCE," INCLUDING THE DISCOVERY OF BEDAQUILINE, NEWLY APPROVED REGIMENS STILL SUFFER FROM SERIOUS SIDE EFFECTS AND CAN BE COST PROHIBITIVE. THEREFORE, NEW CLASSES OF DRUGS WITH NEW MOAS THAT CAN BE COMBINED WITH EXISTING OR NEW TB DRUGS IN THE PIPELINE ARE DESPERATELY NEEDED. THE SUCCESS OF BEDAQUILINE, WHICH DISRUPTS ENERGY METABOLISM IN MTB AND HAS SHOWN PROMISE IN REDUCING TREATMENT TIMES FOR DR-TB, HAS ACCOMPANIED AN EXPLOSION OF DRUG DISCOVERY TARGETING RESPIRATION IN MTB. IN THIS APPLICATION, FIMBRION PROPOSES TO DEVELOP A THIAZOLINO-PYRIDONE (TZP) SMALL MOLECULE SERIES WITH GROWTH INHIBITORY ACTIVITY AGAINST MTB AS A NOVEL DRUG FOR TREATING TB. WHILE THE TARGET OF THIS COMPOUND SERIES IS CURRENTLY UNKNOWN, TZPS APPEAR TO ACT THROUGH DISRUPTION OF MTB RESPIRATION. INTERESTINGLY, CURRENT TZPS NOT ONLY HAVE DIRECT ANTIMYCOBACTERIAL ACTIVITY, BUT THEY CAN ALSO POTENTIATE THE ACTIVITY OF ISONIAZID (INH), AN IMPORTANT FRONTLINE TB ANTIBIOTIC, EVEN RESTORING INH ACTIVITY AGAINST INH-RESISTANT MTB IN VITRO. OUR PRIMARY GOAL IN THIS PROJECT IS TO DEVELOP A FIRST-IN-CLASS, ORALLY BIOAVAILABLE, ANTIMYCOBACTERIAL TZP COMPOUND THAT COULD BECOME PART OF A NEW FRONTLINE TB DRUG REGIMEN TO HELP SHORTEN THE DURATION OF TREATMENT. CURRENTLY, OUR MOST POTENT TZP COMPOUNDS HAVE SUB-MICROMOLAR GROWTH INHIBITION POTENCY IN VITRO, AND FAVORABLE DRUG-LIKE PROPERTIES. THEREFORE, OUR PRIMARY PHASE I GOAL WILL BE TO IMPROVE GROWTH INHIBITION POTENCY WHILE MAINTAINING AND/OR IMPROVING THE DRUG-LIKE PROPERTIES OF THE LEAD COMPOUNDS TO ENABLE TESTING OF OPTIMIZED COMPOUNDS IN AN ANIMAL MODEL OF MTB INFECTION. SPECIFICALLY, WE WILL 1) USE MEDICINAL CHEMISTRY DRUG DESIGN STRATEGIES TO IMPROVE IN VITRO POTENCY, METABOLIC STABILITY, AND SOLUBILITY, AND WILL ESTABLISH IN VIVO PHARMACOKINETIC (PK) PROFILES (INCLUDING ORAL BIOAVAILABILITY) FOR OPTIMIZED TZPS IN MICE; AND 2) INVESTIGATE THE IN VITRO AND IN VIVO EFFICACY OF PRIORITIZED LEAD TZPS AND GENERATE SPONTANEOUS MUTANTS RESISTANT TO THESE COMPOUNDS TO BETTER UNDERSTAND THE BACTERIAL TARGET AND MOA. AS WE HAVE FOUND THAT THE ANTIMYCOBACTERIAL POTENCY OF OUR TZPS TRACKS WITH THEIR ABILITY TO POTENTIATE INH, WE WILL CONTINUE TO SPOT-CHECK THIS SECONDARY PROPERTY THROUGHOUT THE OPTIMIZATION OF OUR TZPS. UPON COMPLETION OF THIS PROJECT, WE EXPECT TO IDENTIFY AN ADVANCED LEAD TZP COMPOUND WITH DEMONSTRATED EFFICACY IN A MOUSE MODEL OF ACUTE TB, WHICH COULD BE FURTHER DEVELOPED IN A FUTURE PHASE II SBIR PROJECT AS PART OF A COMBINATION THERAPY FOR TREATING BOTH DS- AND DR-TB.