Pharmaceutical Control of the Microbiome

The intestinal microbiota encode millions of genes that represent unique pharmaceutical targets for human diseases from neurological disorders to drug toxicity. We are interested in the role intestinal microbiota play in reactivating compounds that have been inactivated through glucuronidation. In particular, the chemotherapy drug CPT‐11 is inactivated by UGTs in the liver and then reactivated by bacterial Β‐glucuronidases in the large intestine resulting in dose‐limiting diarrhea. We characterized the structure and function of three Β‐glucuronidase enzymes from different bacteria and showed that a key bacterial loop allows for selective inhibition of these enzymes versus the human enzyme orthologue. We have developed, using chemical biology, novel inhibitors that potently and non‐lethally inhibit bacterial Β‐glucuronidases and stop drug toxicity of CPT‐11 in mouse models. We also examined the toxicity caused by the nonsteroidal anti‐inflammatory drugs (NSAIDs) diclofenac, ketoprofen, and indomethacin. These drugs were also hypothesized to be reactivated by bacterial Β‐glucuronidases, resulting in the acute longitudinal small intestinal ulcers that causer 40% of NSAID‐associated deaths. We found our inhibitors are also effective against this type of drug toxicity and alleviated the intestinal ulcers seen in mouse models. Thus, we have established that the microbiome contains targets for non‐lethal pharmacology to address acute problems of human health. Funding from NIH CA98468 and NSF Graduate Research Fellowship