Pharmacomicrobiomics: The Frontier of Interindividual Variability in Drug Response

Univ Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

Abstract

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Many medications are modified by intestinal bacteria, positioning them as an emerging and signif- icant driver of overall drug response (efficacy and toxicity) beyond host factors. Considering the importance of bacterial drug metabolism during preclinical development will uncover drug-induced toxicities in relevant tissues, prompt lead retooling and reduce adverse events in human trials. My career goal is to develop pharmacomicrobiomics, the emerging study of drug-microbiota interac- tions that drive variable drug responses. My research goal is to develop a mechanistic under- standing of how bacterial enzymes mediate toxicity and adverse effects of drugs, and to devise strategies to reduce prevent, or treat microbe-mediated drug toxicities in organs involved in drug disposition. Over the next five years, the MIRA will support my efforts to utilize the bacterial en- zyme β-glucuronidase (GUS) as a tool to elucidate mechanisms by which bacterial drug metabo- lism 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 known, genetic manipulation of many GUS encoding bac- teria 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 gut microbiota contribute to interindividual variability in bacterial reactivation of drug-glucuronide conjugates. Program 2 will test the hypothesis that drug disposition-associated tissues derived from different people 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 gut inju- ry. This foundational work will facilitate addition of bacterial drug metabolism into future physiolo- gy-based pharmacokinetic modeling to aid accurate prediction of drug side effects and efficacy. The proposed research is significant as it will systematically interrogate the contribution of bac- terial 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 to improve precision medicine.