Bacterial Inactivation of the Anticancer Drug Doxorubicin

SummaryMicrobes 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.

► Bacterial resistome concept has been expanded to include antineoplastic drugs ► NADH dehydrogenase of WAC04685 catalyzes degradation of doxorubicin ► Enzymatic degradation product, 7-deoxydoxorubicinolone, is nontoxic to bacteria ► Establishes environmental bacteria as source of antineoplastic modifying agents