Molecular insights into microbial β-glucuronidase inhibition to abrogate CPT-11 toxicity

Adam B. Roberts, Bret D. Wallace, Madhu Kumar Venkatesh, Sridhar Mani, Matthew R. Redinbo

Research output: Contribution to journalArticle

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Abstract

Bacterial β-glucuronidases expressed by the symbiotic intestinal microbiota appear to play important roles in druginduced epithelial cell toxicity in the gastrointestinal (GI) tract. For the anticancer drug CPT-11 (irinotecan) and the nonsteroidal anti-inflammatory drug diclofenac, it has been shown that removal of the glucuronide moieties from drug metabolites by bacterial β-glucuronidases in the GI lumen can significantly damage the intestinal epithelium. Furthermore, selective disruption of bacterial β-glucuronidases by small molecule inhibitors alleviates these side effects, which, for CPT-11 {7-ethyl-10-[4-(1-piperidino)-1-piperidino]}, can be dose limiting. Here we characterize novel microbial β-glucuronidase inhibitors that inhibit Escherichia coli β-glucuronidase in vitro with Ki values between 180 nM and 2 μM, and disrupt the enzyme in E. coli cells, with EC50 values as low as 300 nM. All compounds are selective for E. coli β-glucuronidase without inhibiting purified mammalian β-glucuronidase, and they do not impact the survival of either bacterial or mammalian cells. The 2.8 Å resolution crystal structure of one inhibitor bound to E. coli β-glucuronidase demonstrates that it contacts and orders only a portion of the "bacterial loop" present in microbial, but not mammalian, β-glucuronidases. The most potent compound examined in this group was found to protect mice against CPT-11-induced diarrhea. Taken together, these data advance our understanding of the chemical and structural basis of selective microbial β-glucuronidase inhibition, which may improve human drug efficacy and toxicity.

Original languageEnglish (US)
Pages (from-to)208-217
Number of pages10
JournalMolecular Pharmacology
Volume84
Issue number2
DOIs
StatePublished - Aug 2013

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irinotecan
Glucuronidase
Escherichia coli
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

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Molecular insights into microbial β-glucuronidase inhibition to abrogate CPT-11 toxicity. / Roberts, Adam B.; Wallace, Bret D.; Venkatesh, Madhu Kumar; Mani, Sridhar; Redinbo, Matthew R.

In: Molecular Pharmacology, Vol. 84, No. 2, 08.2013, p. 208-217.

Research output: Contribution to journalArticle

Roberts, Adam B. ; Wallace, Bret D. ; Venkatesh, Madhu Kumar ; Mani, Sridhar ; Redinbo, Matthew R. / Molecular insights into microbial β-glucuronidase inhibition to abrogate CPT-11 toxicity. In: Molecular Pharmacology. 2013 ; Vol. 84, No. 2. pp. 208-217.
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