Transformation of the Anticancer Drug Doxorubicin in the Human Gut Microbiome
| Autor: | Jennifer T. Lau, Michael G. Surette, Julie Perry, Gerard D. Wright, Austin Yan, Lesley T. MacNeil, Elizabeth J. Culp |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Klebsiella pneumoniae Antineoplastic Agents Biology medicine.disease_cause Microbiology 03 medical and health sciences 0302 clinical medicine Drug Resistance Bacterial medicine Animals Humans Doxorubicin Anaerobiosis Genetic Testing Microbiome Escherichia coli Biotransformation Genetic Association Studies Caenorhabditis elegans chemistry.chemical_classification biology.organism_classification Raoultella planticola Gastrointestinal Microbiome 3. Good health 030104 developmental biology Infectious Diseases Enzyme chemistry 030220 oncology & carcinogenesis Inactivation Metabolic Bacteria medicine.drug |
| Zdroj: | ACS Infectious Diseases. 4:68-76 |
| ISSN: | 2373-8227 |
| DOI: | 10.1021/acsinfecdis.7b00166 |
| Popis: | 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 Raoultella planticola as a potent inactivator under anaerobic conditions. We demonstrate that R. planticola deglycosylates doxorubicin to metabolites 7-deoxydoxorubicinol and 7-deoxydoxorubicinolone via a reductive deglycosylation mechanism. We further show that doxorubicin is degraded anaerobically by Klebsiella pneumoniae and Escherichia coli BW25113 and present evidence that this phenotype is dependent on molybdopterin-dependent enzyme(s). Deglycosylation of doxorubicin by R. planticola under anaerobic conditions is found to reduce toxicity to the model species Caenorhabditis elegans, providing a model to begin understanding the role of doxorubicin metabolism by microbes in the human gut. Understanding the in vivo 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. |
| Databáze: | OpenAIRE |
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