Structure and Inhibition of Microbiome β-Glucuronidases Essential to the Alleviation of Cancer Drug Toxicity

Area of Science:

• Microbiology
• Structural Biology
• Pharmacology

Background:

• Bacterial beta-glucuronidases contribute to drug-induced gastrointestinal toxicity.
• Selective inhibition of these enzymes shows promise in mitigating this toxicity, as seen with irinotecan in mice.

Purpose of the Study:

• To elucidate the structural and functional diversity of bacterial beta-glucuronidases.
• To characterize inhibitors targeting these enzymes and assess their impact on drug pharmacokinetics.

Main Methods:

• X-ray crystallography was used to determine the structures of beta-glucuronidases from Streptococcus agalactiae, Clostridium perfringens, and Escherichia coli.
• Biochemical characterization of beta-glucuronidase from Bacteroides fragilis was performed.
• Inhibitor design and testing were conducted, along with pharmacokinetic studies in mice.

Main Results:

• Crystal structures revealed conserved yet distinct active site features among different bacterial species.
• Functional diversity in catalytic activity and inhibitor susceptibility was observed.
• Designed inhibitors induced significant conformational changes in enzyme active sites.
• Beta-glucuronidase inhibition did not alter the serum pharmacokinetics of irinotecan or its metabolites in mice.

Conclusions:

• Microbial beta-glucuronidases exhibit functional diversity, presenting varied inhibition profiles.
• Targeting bacterial beta-glucuronidases is a viable strategy for managing drug-induced gastrointestinal toxicity.
• Further research into these enzymes and their inhibitors can lead to improved therapeutic outcomes.