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Blocking Interfering Microbes
Irinotecan is a widely used anticancer pro-drug that is converted in the liver into the active form, but when it gets into the gut, the normally benign microbial flora can convert it into the toxic form, which kills the rapidly multiplying gut epithelium as it would kill rapidly dividing tumor cells, and thus causes diarrhea. Wallace et al. (p. 831; see the Perspective by Patel and Kaufmann) used high-throughput screening to identify inhibitors that target the offending bacterial enzyme, β-glucuronidase, without killing the bacteria or affecting orthologous mammalian enzymes. Crystal structures revealed the molecular basis of selectivity, and in vivo studies showed that an inhibitor protected mice from irinotecan-induced toxicity.
Abstract
The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial β-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial β-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 β-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.
