Project Grant R35GM155168

PHARMACOMICROBIOMICS: THE FRONTIER OF INTERINDIVIDUAL VARIABILITY IN DRUG RESPONSE - PROJECT SUMMARY MANY MEDICATIONS FOR DIVERSE INDICATIONS ARE MODIFIED BY INTESTINAL BACTERIA, POSITIONING THEM AS AN EMERGING AND SIGNIFICANT DRIVER OF OVERALL DRUG RESPONSE (EFFICACY AND TOXICITY) BEYOND HOST FACTORS E.G. ETHNICITY, GENETICS, SEX, AND AGE. CONSIDERING THE IMPORTANCE OF BACTERIAL DRUG METABOLISM DURING PRECLINICAL DEVELOPMENT WILL UNCOVER DRUG-INDUCED TOXICITIES IN RELEVANT TISSUES, PROMPTING LEAD RETOOLING, AND PRECLUDING ADVERSE EVENTS IN HUMAN TRIALS. MY CAREER GOAL IS TO DEVELOP PHARMACOMICROBIOMICS, THE EMERGING STUDY OF DRUG-MICROBIOTA INTERACTIONS THAT DRIVE VARIABLE DRUG RESPONSES. MY RESEARCH GOAL IS TO DEVELOP A MECHANISTIC UNDERSTANDING OF HOW BACTERIAL ENZYMES MEDIATE TOXICITY AND ADVERSE EFFECTS OF VARIOUS DRUGS IN ETHNICALLY DIVERSE POPULATIONS, AND TO DEVISE STRATEGIES TO MITIGATE, PREVENT, OR TREAT MICROBE-MEDIATED DRUG TOXICITIES IN ORGANS INVOLVED IN DRUG DISPOSITION. OVER THE NEXT FIVE YEARS, THE MAXIMIZING INVESTIGATORS' RESEARCH AWARD FOR EARLY STAGE INVESTIGATORS WILL SUPPORT MY EFFORTS TO UTILIZE THE BACTERIAL ENZYME B-GLUCURONIDASE (GUS) AS A TOOL TO ELUCIDATE MECHANISMS BY WHICH BACTERIAL DRUG METABOLISM ALTERS HOST PHYSIOLOGY. GUSS HYDROLYZE AND REACTIVATE GLUCURONIDE-CONJUGATED DRUGS FORMED BY PHASE II METABOLISM OF HOST UGT ENZYMES. DECONJUGATED AGLYCONES ARE ACTIVE AND CAN BE TOXIC TO TISSUES INVOLVED IN DRUG DISPOSITION, E.G. THE INTESTINES. MOLECULAR AND STRUCTURAL FEATURES DRIVING GUS' SUBSTRATE PREFERENCES ARE ELUCIDATED, GENETIC MANIPULATION OF MANY GUS- ENCODING BACTERIA IS FEASIBLE, AND SELECTIVE GUS INHIBITORS ARE IN PRECLINICAL DEVELOPMENT. COMBINING THIS FOUNDATIONAL POSTDOCTORAL WORK WITH HIGH-THROUGHPUT PRIMARY CELL CULTURE PLATFORMS, I PROPOSE TWO INTERRELATED RESEARCH PROGRAMS: PROGRAM 1 WILL TEST THE HYPOTHESIS THAT INCLUSION OF MICROBIOTA FROM DIVERSE POPULATIONS WILL REVEAL THE RANGE OF INTERINDIVIDUAL VARIABILITY IN BACTERIA REACTIVATION OF VARIOUS DRUG-GLUCURONIDE CONJUGATES. PROGRAM 2 WILL TEST THE HYPOTHESIS THAT DRUG DISPOSITION-ASSOCIATED TISSUES DERIVED FROM DIVERSE ETHNIC POPULATIONS VARY IN THEIR SUSCEPTIBILITY TO BACTERIAL DRUG METABOLISM. THIS PROPOSAL IS THE FIRST SYSTEMATIC ANALYSIS OF BACTERIAL METABOLISM OF HOST PHASE II CONJUGATES, AND THEIR CONTRIBUTION TO DRUG-INDUCED INJURY IN DIVERSE ETHNIC POPULATIONS. THIS FOUNDATIONAL WORK WILL FACILITATE ADDITION OF BACTERIAL DRUG INTO FUTURE PHYSIOLOGY- BASED PHARMACOKINETIC MODELING THAT CAN AID IN THE ACCURATE ACCURATE PREDICTION OF DRUG SIDE EFFECTS AND EFFICACY. THE PROPOSED RESEARCH IS SIGNIFICANT AS IT WILL SYSTEMATICALLY INTERROGATE THE CONTRIBUTION OF BACTERIAL DRUG METABOLISM TO INTERINDIVIDUAL VARIABILITY IN DRUG RESPONSES. IT WILL DEVELOP PHENOTYPIC BIOMARKERS OF BACTERIAL DRUG REACTIVATION AND RESULTANT DRUG-INDUCED INJURY, AND SERVE AS A PRIMER FOR FUTURE PHARMACOMICROBIOMIC STUDIES. IMPORTANTLY, THIS MIRA PROGRAM WILL UTILIZE SAMPLES FROM HISTORICALLY UNDER- OR UNSTUDIED POPULATIONS INTO THIS EMERGING AND EXCITING NEW REALM OF BIOMEDICAL RESEARCH WITH THE GOAL TO IMPROVE PRECISION MEDICINE FOR ALL.