For public, 20 lines max The GI microbiota is involved in drug metabolism. In most cases, these activities are harmless, however the metabolism of both common drugs (such as NSAIDs) and disease-specific drugs (to treat cancer, for example) is often accompanied by adverse reactions in the lower GI. These reactions can be life-threatening in and of themselves or a cause to discontinue therapy. We demonstrated that bacterial beta-glucuronidase enzymes (GUS) that reside in the lower GI are responsible for lower GI toxicity. These enzymes ?reactivate? drugs that have been targeted for elimination, which in turn causes adverse reactions. Thus, targeting the drug/GUS interaction represents a novel pathway for drug development. This project seeks to develop benchtop methods capable of reproducing biologically relevant systems of both the human host and the bacterial GUS enzymes responsible for toxic reactivation of drug metabolites in the GI. Named the ?Benchtop Symbiome?, this is a cost- effective approach to modeling in vivo drug metabolism, and uses a library of purified GUS enzymes to identify the specific drug/GUS activities for future targeting. Our objectives in this Phase I proposal are to (1) expand our library of purified GUS enzymes to include all representative GUS families, (2) rigorously validate the utility of the Benchtop Symbiome to identify the GUS enzymes with the highest specificity for a candidate drug target and (3) using patient-derived fecal samples as a source of GUS enzymes, evaluate the utility of the Benchtop Symbiome for use in precision medicine approaches. Validation of this new tool will accelerate our ability to fully realize the therapeutic opportunities presented by successfully modulating enzymes in the gut microbiome.
The mammalian microbiome significantly affects drug metabolism. We aim to develop a novel technology for the simple, cost-efficient, production of physiologically relevant drug metabolites in a bench top format. This critical tool can be applied to a range of applications, including the identification of novel drug targets to reduce or eliminate drug-dependent adverse effects in the lower GI.
