The Benchtop Symbiome: developing an integrated mammalian-microbial assay platform to accelerate microbiome-targeted drug discovery

Project SummaryFor publiclines max The GI microbiota is involved in drug metabolismIn most casesthese activities are harmlesshowever the metabolism of both common drugssuch as NSAIDsand disease specific drugsto treat cancerfor exampleis often accompanied by adverse reactions in the lower GIThese reactions can be life threatening in and of themselves or a cause to discontinue therapyWe demonstrated that bacterial beta glucuronidase enzymesGUSthat reside in the lower GI are responsible for lower GI toxicityThese enzymesreactivatedrugs that have been targeted for eliminationwhich in turn causes adverse reactionsThustargeting the drug GUS interaction represents a novel pathway for drug developmentThis 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 GINamed theBenchtop Symbiomethis is a costeffective approach to modeling in vivo drug metabolismand uses a library of purified GUS enzymes to identify the specific drug GUS activities for future targetingOur objectives in this Phase I proposal are toexpand our library of purified GUS enzymes to include all representative GUS familiesrigorously validate the utility of the Benchtop Symbiome to identify the GUS enzymes with the highest specificity for a candidate drug target andusing patient derived fecal samples as a source of GUS enzymesevaluate the utility of the Benchtop Symbiome for use in precision medicine approachesValidation of this new tool will accelerate our ability to fully realize the therapeutic opportunities presented by successfully modulating enzymes in the gut microbiome Project NarrativeThe mammalian microbiome significantly affects drug metabolismWe aim to develop a novel technology for the simplecost efficientproduction of physiologically relevant drug metabolites in a bench top formatThis critical tool can be applied to a range of applicationsincluding the identification of novel drug targets to reduce or eliminate drug dependent adverse effects in the lower GI