Investigating the Role of Symbiotic Bacteria in Mediating GI Toxicity (2012)

Undergraduates: Makani Dollinger, Bret Wallace, Esteban Figueroa Matthew Redinbo, Bruce McClane

Faculty Advisor: Matthew Redinbo
Department: Chemistry

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The common colon cancer chemotherapeutic CPT-11 is associated with severe diarrhea caused by symbiotic bacterial b-glucuronidases that reactivate the drug in the gut. These enzymes were targeted so that the commensal bacteria essential for human health were not killed. Potent bacterial b-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial b-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally, oral administration of an inhibitor protected mice from CPT-11–induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy.