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Antimicrobial Agents and Chemotherapy, July 2008, p. 2428-2434, Vol. 52, No. 7
0066-4804/08/$08.00+0     doi:10.1128/AAC.00084-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

ramR Mutations Involved in Efflux-Mediated Multidrug Resistance in Salmonella enterica Serovar Typhimurium{triangledown}

Yousef M. Abouzeed, Sylvie Baucheron, and Axel Cloeckaert*

INRA, UR1282, Infectiologie Animale et Santé Publique, IASP, Nouzilly F-37380, France

Received 21 January 2008/ Returned for modification 1 April 2008/ Accepted 21 April 2008

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 IS1 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.

* Corresponding author. Mailing address: Unité Infectiologie Animale et Santé Publique site 213, Institut National de la Recherche Agronomique, 37380 Nouzilly, France. Phone: 33-(0)2 47 42 77 50. Fax: 33-(0)2 47 42 77 74. E-mail: cloeckae{at}tours.inra.fr

{triangledown} Published ahead of print on 28 April 2008.

Antimicrobial Agents and Chemotherapy, July 2008, p. 2428-2434, Vol. 52, No. 7
0066-4804/08/$08.00+0     doi:10.1128/AAC.00084-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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