title: The Tetracycline Destructases: A Novel Family of Tetracycline-Inactivating Enzymes.
abstract: Enzymes capable of inactivating tetracycline are paradoxically rare compared with enzymes that inactivate other natural-product antibiotics. We describe a family of flavoenzymes, previously unrecognizable as resistance genes, which are capable of degrading tetracycline antibiotics. From soil functional metagenomic selections, we discovered nine genes that confer high-level tetracycline resistance by enzymatic inactivation. We also demonstrate that a tenth enzyme, an uncharacterized homolog in the human pathogen Legionella longbeachae, similarly inactivates tetracycline. These enzymes catalyze the oxidation of tetracyclines in vitro both by known mechanisms and via previously undescribed activity. Tetracycline-inactivation genes were identified in diverse soil types, encompass substantial sequence diversity, and are adjacent to genes implicated in horizontal gene transfer. Because tetracycline inactivation is scarcely observed in hospitals, these enzymes may fill an empty niche in pathogenic organisms, and should therefore be monitored for their dissemination potential into the clinic.
authors.affiliation: Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO 63108, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Forsberg
authors.affiliation: Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO 63108, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63108, USA.
authors.forename: Sanket
authors.initials: S
authors.lastname: Patel
authors.affiliation: Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA. Electronic address: wencewicz@wustl.edu.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Wencewicz
authors.affiliation: Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO 63108, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63108, USA; Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA. Electronic address: dantas@wustl.edu.
authors.forename: Gautam
authors.initials: G
authors.lastname: Dantas
mesh_terms: D065767:Activation, Metabolic; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D008969:Molecular Sequence Data; D010105:Oxygenases / Q000235:genetics* / Q000378:metabolism*; D012988:Soil Microbiology; D013752:Tetracycline / Q000493:pharmacokinetics* / Q000494:pharmacology; D013753:Tetracycline Resistance / Q000235:genetics*
chemical_list: D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D013752:Tetracycline