MgrA Is a Multiple Regulator of Two New Efflux Pumps inStaphylococcus aureus

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Abstract
In an analysis of the resistance mechanisms of anmgrAmutant, we identified two genes encoding previously undescribed transporters, NorB and Tet38.norBwas 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 themgrAmutant. NorA and NorB shared 30% similarity, and NorB shared 30 and 41% similarities with the Bmr and Blt transporters ofBacillus 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 ofS. aureus. tet38was 1,353 bp and encoded a predicted 49-kDa protein. Overexpression oftet38produced resistance to tetracycline but not to minocycline and other drugs.norBandtet38transcription was negatively regulated by MgrA. Limited binding of MgrA to the promoter regions ofnorBandtet38was demonstrated by gel shift assays, suggesting that MgrA was an indirect regulator ofnorBandtet38expression. ThemgrA norBdouble mutant was reproducibly twofold more susceptible to the tested quinolones than themgrAmutant. ThemgrA tet38double 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 themgrAmutant and that MgrA regulates expression ofnorBandtet38in addition to its role in regulation ofnorAexpression.