Affiliation:
1. INRA, UR1282, Infectiologie Animale et Santé Publique, IASP, Nouzilly F-37380, France
Abstract
ABSTRACT
In the sequenced genome of
Salmonella enterica
serovar Typhimurium strain LT2, an open reading frame (STM0580) coding for a putative regulatory protein of the TetR family is found upstream of the
ramA
gene. Overexpression of
ramA
results in increased expression of the AcrAB efflux pump and, consequently, multidrug resistance (MDR) in several bacterial species. The inactivation of the putative regulatory protein gene upstream of
ramA
in a susceptible serovar Typhimurium strain resulted in an MDR phenotype with fourfold increases in the MICs of unrelated antibiotics, such as quinolones/fluoroquinolones, phenicols, and tetracycline. The inactivation of this gene also resulted in a fourfold increase in the expression of
ramA
and a fourfold increase in the expression of the AcrAB efflux pump. These results indicated that the gene encodes a local repressor of
ramA
and was thus named
ramR
. In contrast, the inactivation of
marR
,
marA
,
soxR
, and
soxS
did not affect the susceptibilities of the strain. In quinolone- or fluoroquinolone-resistant strains of serovar Typhimurium overexpressing AcrAB, several point mutations which resulted in amino acid changes or an in-frame shift were identified in
ramR
; in addition, mutations interrupting
ramR
with an IS
1
element were identified in high-level fluoroquinolone-resistant serovar Typhimurium DT204 strains. One serovar Typhimurium DT104 isolate had a 2-nucleotide deletion in the putative RamR binding site found upstream of
ramA
. These mutations were confirmed to play a role in the MDR phenotype by complementing the isolates with an intact
ramR
gene or by inactivating their respective
ramA
gene. No mutations in the
mar
or
sox
region were found in the strains studied. In conclusion, mutations in
ramR
appear to play a major role in the upregulation of RamA and AcrAB and, consequently, in the efflux-mediated MDR phenotype of serovar Typhimurium.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
145 articles.
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