Elucidating the Interactions between Gut Bacterial β-Glucuronidases and Approved Drugs

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  • Jariwala, Parth Balvant
    • College of Arts and Sciences, Department of Chemistry
Abstract
  • The human gut microbiome contains a plethora of enzymes that metabolize a myriad ofdiet-derived, host-derived, and therapeutic agents. Metabolism of therapeutic agents by gutmicrobiota can result in altered drug efficacy and toxicity. An important bacterial enzymeinvolved in the metabolism of drugs in the gastrointestinal tract is the gut bacterial β-glucuronidase (GUS). One notable example of drug metabolism by GUS enzymes is thereactivation of the active metabolite of the chemotherapeutic irinotecan, SN-38, which causessevere, dose limiting toxicity in patients. Recent analysis of the Human Microbiome Projectrevealed 279 unique GUS isoforms encoded by gut microbiota. Elucidating the exact GUSisoform reactivating drugs like SN-38 can lead to precise dosing of drugs on an individual basisand reduce gut microbiota-mediated toxic side effects. In this dissertation, a novel activity-basedproteomics strategy is used to identify the exact GUS isoform responsible for the reactivation ofSN-38. In addition to the metabolism of drugs by GUS enzymes, another important interaction isthe inhibition of GUS enzymes by FDA-approved drugs. Inhibition of GUS activity can result inaltered homeostasis because GUS enzymes also reactivate host-derived endobiotics and processdiet-derived glucuronic acid-containing polysaccharides. We present data showing that approveddrugs with a particular chemical scaffold can inhibit the activity of GUS enzymes. Altering theabundance or activity of GUS enzymes can potentially reduce GUS-mediated metabolism oftherapeutics. We next present data on how dietary fiber influences the abundance of GUSivencoding gut bacterial species. These data provide information on how diet can potentially beused to modulate GUS activity in the gut. In addition to diet, another approach to reduce themetabolism of drugs by GUS and other gut microbial enzymes is using small moleculeadjuvants. The final chapter outlines a chemoproteomics platform that could be used to discoverselective small molecule inhibitors that reduce the metabolism of any drug of interest. Together,the work presented here expands on our knowledge of GUS-drug interactions, discusses methodsto alter GUS activity, and outlines a chemoproteomics platform to identify small moleculeinhibitors of gut enzymes.
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  • In Copyright - Educational Use Permitted
Advisor
  • Redinbo, Matthew R
  • Pielak, Gary J
  • Li, Bo
  • Hicks, Leslie M
  • James, Lindsey I
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2021
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