title: Effects of efflux transporter genes on susceptibility of Escherichia coli to tigecycline (GAR-936).
abstract: The activity of tigecycline, 9-(t-butylglycylamido)-minocycline, against Escherichia coli KAM3 (acrB) strains harboring plasmids encoding various tetracycline-specific efflux transporter genes, tet(B), tet(C), and tet(K), and multidrug transporter genes, acrAB, acrEF, and bcr, was examined. Tigecycline showed potent activity against all three Tet-expressing, tetracycline-resistant strains, with the MICs for the strains being equal to that for the host strain. In the Tet(B)-containing vesicle study, tigecycline did not significantly inhibit tetracycline efflux-coupled proton translocation and at 10 microM did not cause proton translocation. This suggests that tigecycline is not recognized by the Tet efflux transporter at a low concentration; therefore, it exhibits significant antibacterial activity. These properties can explain its potent activity against bacteria with a Tet efflux resistance determinant. Tigecycline induced the Tet(B) protein approximately four times more efficiently than tetracycline, as determined by Western blotting, indicating that it is at least recognized by a TetR repressor. The MICs for multidrug efflux proteins AcrAB and AcrEF were increased fourfold. Tigecycline inhibited active ethidium bromide efflux from intact E. coli cells overproducing AcrAB. Therefore, tigecycline is a possible substrate of AcrAB and its close homolog, AcrEF, which are resistance-modulation-division-type multicomponent efflux transporters.
authors.affiliation: Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hirata
authors.forename: Asami
authors.initials: A
authors.lastname: Saito
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Nishino
authors.forename: Norihisa
authors.initials: N
authors.lastname: Tamura
authors.forename: Akihito
authors.initials: A
authors.lastname: Yamaguchi
mesh_terms: D015153:Blotting, Western; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D004996:Ethidium / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives* / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D011522:Protons; D011796:Quinacrine; D013753:Tetracycline Resistance / Q000235:genetics*; D013754:Tetracyclines / Q000494:pharmacology*; D000078304:Tigecycline
chemical_list: D004996:Ethidium; D008911:Minocycline; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011522:Protons; D011796:Quinacrine; D013754:Tetracyclines; D000078304:Tigecycline