title: Fluoroquinolone-modifying enzyme: a new adaptation of a common aminoglycoside acetyltransferase.
abstract: Antimicrobial-modifying resistance enzymes have traditionally been class specific, having coevolved with the antibiotics they inactivate. Fluoroquinolones, antimicrobial agents used extensively in medicine and agriculture, are synthetic and have been considered safe from naturally occurring antimicrobial-modifying enzymes. We describe reduced susceptibility to ciprofloxacin in clinical bacterial isolates conferred by a variant of the gene encoding aminoglycoside acetyltransferase AAC(6')-Ib. This enzyme reduces the activity of ciprofloxacin by N-acetylation at the amino nitrogen on its piperazinyl substituent. Although approximately 30 variants of this gene have been reported since 1986, the two base-pair changes responsible for the ciprofloxacin modification phenotype are unique to this variant, first reported in 2003 and now widely disseminated. An intense increase in the medical use of ciprofloxacin seems to have been accompanied by a notable development: a single-function resistance enzyme has crossed class boundaries, and is now capable of enzymatically undermining two unrelated antimicrobial agents, one of them fully synthetic.
authors.affiliation: Harvard Medical School, Division of Infectious Diseases, Massachusetts General Hospital, 55 Fruit St, GRJ 512, Boston, Massachusetts 02114, USA.
authors.forename: Ari
authors.initials: A
authors.lastname: Robicsek
authors.forename: Jacob
authors.initials: J
authors.lastname: Strahilevitz
authors.forename: George A
authors.initials: GA
authors.lastname: Jacoby
authors.forename: Mark
authors.initials: M
authors.lastname: Macielag
authors.forename: Darren
authors.initials: D
authors.lastname: Abbanat
authors.forename: Chi Hye
authors.initials: CH
authors.lastname: Park
authors.forename: Karen
authors.initials: K
authors.lastname: Bush
authors.forename: David C
authors.initials: DC
authors.lastname: Hooper
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000737:chemistry* / Q000235:genetics*; D000595:Amino Acid Sequence; D000890:Anti-Infective Agents / Q000494:pharmacology; D002939:Ciprofloxacin / Q000494:pharmacology; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D004352:Drug Resistance, Microbial; D004798:Enzymes / Q000737:chemistry*; D004926:Escherichia coli / Q000235:genetics* / Q000378:metabolism; D024841:Fluoroquinolones / Q000737:chemistry*; D005821:Genetic Techniques; D014644:Genetic Variation; D007700:Kinetics; D008956:Models, Chemical; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009584:Nitrogen / Q000737:chemistry; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013997:Time Factors
chemical_list: D000890:Anti-Infective Agents; D004798:Enzymes; D024841:Fluoroquinolones; D002939:Ciprofloxacin; D000123:Acetyltransferases; C019681:aminoglycoside acetyltransferase; D009584:Nitrogen