Transformation of the Anticancer Drug Doxorubicin in the Human Gut Microbiome

Bacteria living in the human gut are implicated in the etiology of several diseases. Moreover, dozens of drugs are metabolized by elements of the gut microbiome, which may have further implications for human health. Here, we screened a collection of gut isolates for their ability to inactivate the widely used antineoplastic drug doxorubicin and identified a strain of <i>Raoultella planticola</i> as a potent inactivator under anaerobic conditions. We demonstrate that <i>R. planticola</i> deglycosylates doxorubicin to metabolites 7-deoxydoxorubicinol and 7-deoxydoxorubicinolone via a reductive deglycosylation mechanism. We further show that doxorubicin is degraded anaerobically by <i>Klebsiella pneumoniae</i> and <i>Escherichia coli</i> BW25113 and present evidence that this phenotype is dependent on molybdopterin-dependent enzyme(s). Deglycosylation of doxorubicin by <i>R. planticola</i> under anaerobic conditions is found to reduce toxicity to the model species <i>Caenorhabditis elegans</i>, providing a model to begin understanding the role of doxorubicin metabolism by microbes in the human gut. Understanding the <i>in vivo</i> metabolism of important therapeutics like doxorubicin by the gut microbiome has the potential to guide clinical dosing to maximize therapeutic benefit while limiting undesirable side effects

Additinal file 1:

In the supplement Material Section results from the protein purification and respective SDS-PAGE as well as the data from the stimulation of a SIRT6 mutant on MYH and APE1 activities are presented