title: Bacterial inactivation of the anticancer drug doxorubicin.
abstract: Microbes are exposed to compounds produced by members of their ecological niche, including molecules with antibiotic or antineoplastic activities. As a result, even bacteria that do not produce such compounds can harbor the genetic machinery to inactivate or degrade these molecules. Here, we investigated environmental actinomycetes for their ability to inactivate doxorubicin, an aminoglycosylated anthracycline anticancer drug. One strain, Streptomyces WAC04685, inactivates doxorubicin via a deglycosylation mechanism. Activity-based purification of the enzymes responsible for drug inactivation identified the NADH dehydrogenase component of respiratory electron transport complex I, which was confirmed by gene inactivation studies. A mechanism where reduction of the quinone ring of the anthracycline by NADH dehydrogenase leads to deglycosylation is proposed. This work adds anticancer drug inactivation to the enzymatic inactivation portfolio of actinomycetes and offers possibilities for novel applications in drug detoxification.
authors.affiliation: M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, DeGroote School of Medicine, McMaster University, 1280 Main Street W, Hamilton, ON L8N 4K1, Canada.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Westman
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Canova
authors.forename: Inas J
authors.initials: IJ
authors.lastname: Radhi
authors.forename: Kalinka
authors.initials: K
authors.lastname: Koteva
authors.forename: Inga
authors.initials: I
authors.lastname: Kireeva
authors.forename: Nicholas
authors.initials: N
authors.lastname: Waglechner
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Wright
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001483:Base Sequence; D004317:Doxorubicin / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D006031:Glycosylation / Q000187:drug effects; D008969:Molecular Sequence Data; D009245:NADH Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D013302:Streptomyces / Q000187:drug effects* / Q000201:enzymology
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D009245:NADH Dehydrogenase