The gut microbiota contains millions of unique gene products that encode factors that directly and indirectly impact human physiology and disease. Here we focus on gut microbial glucuronidases that reverse the action of mammalian drug and endobiotic metabolizing glucuronidating factors. We show that these bacterial glucuronidase (GUS) enzymes can be potently, selectively and non-lethally inhibited to alleviate toxicities associated with cancer and pain medications. Surprisingly, the novel inhibitors designed employ a secondary amine that highjacks the catalytic cycle of the GUS glycoside hydrolase active site. Furthermore, a wide range of current drugs with the same chemical motif were also found to have the same impact on gut microbial enzymes. Taken together, these results show that the gut microbiota contain druggable targets and that extant therapeutics also have significant effects on a core function of the gut microbiome.
Wednesday, June 2, 2021 - 4:00pm
Prof. Matt Redinbo
UNC Chapel Hill