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Antimicrobial Agents and Chemotherapy, June 2004, p. 2179-2184, Vol. 48, No. 6
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.6.2179-2184.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Effects of Efflux Transporter Genes on Susceptibility of Escherichia coli to Tigecycline (GAR-936)

Takahiro Hirata,1,2,3 Asami Saito,1,2 Kunihiko Nishino,1,2,3,{dagger} Norihisa Tamura,1,2,3 and Akihito Yamaguchi1,2,3*

Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, Osaka University, Ibaraki,1 CREST, Japan Science and Technology Corporation, Osaka 567-0047,3 Faculty of Pharmaceutical Science, Osaka University, Suita, Osaka 565-0871, Japan2

Received 10 September 2003/ Returned for modification 5 November 2003/ Accepted 9 February 2004

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 µM 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.

* Corresponding author. Mailing address: Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan. Phone: 81-6-6879-8545. Fax: 81-6-6879-8549. E-mail: akihito{at}sanken.osaka-u.ac.jp.

{dagger} Present address: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.

Antimicrobial Agents and Chemotherapy, June 2004, p. 2179-2184, Vol. 48, No. 6
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.6.2179-2184.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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