title: Tigecycline Efflux as a Mechanism for Nonsusceptibility in Acinetobacter baumannii.
abstract: Tigecycline has an extended spectrum of in vitro antimicrobial activities, including that against multidrug-resistant Acinetobacter. After identifying bloodstream isolates of Acinetobacter with reduced susceptibilities to tigecycline, we performed a study to assess tigecycline efflux mediated by the resistance-nodulation-division-type transporter AdeABC. After exposure of two tigecycline-nonsusceptible isolates to the efflux pump inhibitor phenyl-arginine-beta-naphthylamide (PABN), a fourfold reduction in the tigecycline MIC was observed. Both tigecycline-susceptible and -nonsusceptible isolates were found to carry the gene coding for the transmembrane component of the AdeABC pump, adeB, and the two-component regulatory system comprising adeS and adeR. Previously unreported point mutations were identified in the regulatory system in tigecycline-nonsusceptible isolates. Real-time PCR identified 40-fold and 54-fold increases in adeB expression in the two tigecycline-nonsusceptible isolates compared to that in a tigecycline-susceptible isolate. In vitro exposure of a tigecycline-susceptible clinical strain to tigecycline caused a rapid rise in the MIC of tigecycline from 2 microg/ml to 24 microg/ml, which was reversible with PABN. A 25-fold increase in adeB expression was observed in a comparison between this tigecycline-susceptible isolate and its isogenic tigecycline-nonsusceptible mutant. These results indicate that an efflux-based mechanism plays a role in reduced tigecycline susceptibility in Acinetobacter.
authors.affiliation: Division of Infectious Diseases, Beth Israel Deaconess Medical Center and Harvard Medical School, 110 Francis St., LMOB Suite GB, Boston, MA 02215, USA. apeleg@bidmc.harvard.edu
authors.forename: Anton Y
authors.initials: AY
authors.lastname: Peleg
authors.forename: Jennifer
authors.initials: J
authors.lastname: Adams
authors.forename: David L
authors.initials: DL
authors.lastname: Paterson
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D024881:Drug Resistance, Bacterial; D004996:Ethidium / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D000078304:Tigecycline
chemical_list: C492436:AdeA protein, Acinetobacter baumannii; C445684:AdeB protein, Acinetobacter baumannii; C492437:AdeC protein, Acinetobacter baumannii; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; D000078304:Tigecycline; D004996:Ethidium; D008911:Minocycline