Affiliation:
1. Division of Infectious Diseases and Medical Services, Massachusetts General Hospital
2. Harvard Medical School, Boston, Massachusetts
3. Department of Infectious Diseases, Wyeth Research, Pearl River, New York
Abstract
ABSTRACT
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.
Publisher
American Society for Microbiology
Subject
Molecular Biology,Microbiology
Cited by
240 articles.
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