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Journal of Bacteriology, October 2001, p. 5639-5644, Vol. 183, No. 19
0021-9193/01/$04.00+0   DOI: 10.1128/JB.183.19.5639-5644.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Novel Macrolide-Specific ABC-Type Efflux Transporter in Escherichia coli

Nobuyoshi Kobayashi,1,2 Kunihiko Nishino,1,2,3 and Akihito Yamaguchi1,2,3,*

Faculty of Pharmaceutical Science, Osaka University, Suita, Osaka 565-0871,2 and Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, Osaka University, Ibaraki,1 and CREST, Japan Science and Technology Corporation,3 Osaka 567-0047, Japan

Received 12 March 2001/Accepted 10 July 2001

In the Escherichia coli genome, five putative open reading frame (ORF) clusters, mdlAB, ybjYZ, yddA, yojHI, and yhiH, have been assumed to be possible genes for ABC drug efflux transporters (I. T. Paulsen, M. K. Sliwinski, and M. H. Saier, Jr., J. Mol. Biol. 277:573-592, 1998). We cloned all of these ORFs in multicopy plasmids and investigated the drug resistance of drug-supersensitive host cells lacking constitutive multidrug efflux transporter genes acrAB. Among them, only ybjYZ gave significant erythromycin resistance and significantly decreased the accumulation of [14C]erythromycin. Therefore, ybjYZ was renamed macAB (macrolide-specific ABC-type efflux carrier). Plasmids carrying both the macA and -B genes conferred resistance against macrolides composed of 14- and 15-membered lactones but no or weak resistance against 16-membered ones. Neither of the two genes produced resistance alone. The DNA sequence suggests that MacB is an integral membrane protein with four transmembrane segments and one nucleotide-binding domain, while MacA belongs to a membrane fusion protein (MFP) family with a signal-like sequence at its N terminus. The expression of the histidine-tagged proteins confirmed that MacB is an integral membrane protein and MacA is a peripheral membrane protein. In addition, MacAB required TolC for its function in a way similar to that of most of the MFP-dependent transporters in E. coli. MacB is thus a novel ABC-type macrolide efflux transporter which functions by cooperating with the MFP MacA and the multifunctional outer membrane channel TolC. This is the first case of an experimentally identified ABC antibiotic efflux transporter in gram-negative organisms.

* 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.

Journal of Bacteriology, October 2001, p. 5639-5644, Vol. 183, No. 19
0021-9193/01/$04.00+0   DOI: 10.1128/JB.183.19.5639-5644.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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