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Journal of Bacteriology, April 2005, p. 2395-2405, Vol. 187, No. 7
0021-9193/05/$08.00+0     doi:10.1128/JB.187.7.2395-2405.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

MgrA Is a Multiple Regulator of Two New Efflux Pumps in Staphylococcus aureus{dagger}

Q. C. Truong-Bolduc,1,2 P. M. Dunman,3 J. Strahilevitz,1,2 S. J. Projan,3 and D. C. Hooper1,2*

Division of Infectious Diseases and Medical Services, Massachusetts General Hospital,1 Harvard Medical School, Boston, Massachusetts,2 Department of Infectious Diseases, Wyeth Research, Pearl River, New York3

Received 18 October 2004/ Accepted 23 December 2004

In an analysis of the resistance mechanisms of an mgrA mutant, we identified two genes encoding previously undescribed transporters, NorB and Tet38. norB was 1,392 bp and encoded a predicted 49-kDa protein. When overexpressed, NorB led to an increase in resistance to hydrophilic quinolones, ethidium bromide, and cetrimide and also to sparfloxacin, moxifloxacin, and tetracycline, a resistance phenotype of the mgrA mutant. NorA and NorB shared 30% similarity, and NorB shared 30 and 41% similarities with the Bmr and Blt transporters of Bacillus subtilis, respectively. The second efflux pump was a more selective transporter that we have called Tet38, which had 46% similarity with the plasmid-encoded TetK efflux transporter of S. aureus. tet38 was 1,353 bp and encoded a predicted 49-kDa protein. Overexpression of tet38 produced resistance to tetracycline but not to minocycline and other drugs. norB and tet38 transcription was negatively regulated by MgrA. Limited binding of MgrA to the promoter regions of norB and tet38 was demonstrated by gel shift assays, suggesting that MgrA was an indirect regulator of norB and tet38 expression. The mgrA norB double mutant was reproducibly twofold more susceptible to the tested quinolones than the mgrA mutant. The mgrA tet38 double mutant became more susceptible to tetracycline than the wild-type parent strain. These data demonstrate that overexpression of NorB and Tet38 contribute, respectively, to the hydrophobic quinolone resistance and the tetracycline resistance of the mgrA mutant and that MgrA regulates expression of norB and tet38 in addition to its role in regulation of norA expression.

* Corresponding author. Mailing address: Division of Infectious Diseases, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114-2696. Phone: (617) 726-3812. Fax: (617) 726-7416. E-mail: dhooper{at}partners.org.

{dagger} Supplemental material for this article may be found at http://jb.asm.org/.

Journal of Bacteriology, April 2005, p. 2395-2405, Vol. 187, No. 7
0021-9193/05/$08.00+0     doi:10.1128/JB.187.7.2395-2405.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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