Transformation of the Anticancer Drug Doxorubicin in the Human Gut Microbiome

Area of Science:

• Microbiology
• Pharmacology
• Biochemistry

Background:

• The human gut microbiome plays a role in disease etiology and drug metabolism.
• Understanding microbial drug metabolism is crucial for human health and therapeutic efficacy.

Purpose of the Study:

• To screen gut bacteria for the ability to inactivate the antineoplastic drug doxorubicin.
• To elucidate the mechanism of doxorubicin inactivation by gut microbes.
• To assess the impact of microbial doxorubicin metabolism on drug toxicity.

Main Methods:

• Screening of gut bacterial isolates for doxorubicin inactivation.
• Identification of active bacterial strains (e.g., Raoultella planticola).
• Biochemical analysis of metabolic pathways (reductive deglycosylation).
• Assessment of drug toxicity in Caenorhabditis elegans models.

Main Results:

• Raoultella planticola was identified as a potent inactivator of doxorubicin under anaerobic conditions.
• R. planticola deglycosylates doxorubicin to 7-deoxydoxorubicinol and 7-deoxydoxorubicinolone via reductive deglycosylation.
• Doxorubicin degradation was also observed in Klebsiella pneumoniae and Escherichia coli, dependent on molybdopterin-related enzymes.
• Anaerobic deglycosylation by R. planticola reduced doxorubicin's toxicity to Caenorhabditis elegans.

Conclusions:

• Gut bacteria, including R. planticola, can metabolize doxorubicin through reductive deglycosylation.
• Microbial metabolism of doxorubicin can reduce its toxicity.
• This research provides a model for understanding gut microbiome-drug interactions and has implications for optimizing cancer therapy dosing.