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Antimicrobial Agents and Chemotherapy, February 2007, p. 535-542, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.00600-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Contribution of Target Gene Mutations and Efflux to Decreased Susceptibility of Salmonella enterica Serovar Typhimurium to Fluoroquinolones and Other Antimicrobials

Sheng Chen,^1, Shenghui Cui,¹ Patrick F. McDermott,² Shaohua Zhao,² David G. White,² Ian Paulsen,³ and Jianghong Meng^1*

Department of Nutrition and Food Science, University of Maryland, College Park, Maryland 20742,¹ Division of Animal and Food Microbiology, Office of Research, Center for Veterinary Medicine, the U.S. Food and Drug Administration, Laurel, Maryland 20708,² The Institute for Genomic Research, Rockville, Maryland 20860³

Received 16 May 2006/ Returned for modification 27 July 2006/ Accepted 3 October 2006

The mechanisms involved in fluoroquinolone resistance in Salmonella enterica include target alterations and overexpression of efflux pumps. The present study evaluated the role of known and putative multidrug resistance efflux pumps and mutations in topoisomerase genes among laboratory-selected and naturally occurring fluoroquinolone-resistant Salmonella enterica serovar Typhimurium strains. Strains with ciprofloxacin MICs of 0.25, 4, 32, and 256 µg/ml were derived in vitro using serovar Typhimurium S21. These mutants also showed decreased susceptibility or resistance to many nonfluoroquinolone antimicrobials, including tetracycline, chloramphenicol, and several ß-lactams. The expression of efflux pump genes acrA, acrB, acrE, acrF, emrB, emrD, and mdlB were substantially increased (2-fold) among the fluoroquinolone-resistant mutants. Increased expression was also observed, but to a lesser extent, with three other putative efflux pumps: mdtB (yegN), mdtC (yegO), and emrA among mutants with ciprofloxacin MICs of 32 µg/ml. Deletion of acrAB or tolC in S21 and its fluoroquinolone-resistant mutants resulted in increased susceptibility to fluoroquinolones and other tested antimicrobials. In naturally occurring fluoroquinolone-resistant serovar Typhimurium strains, deletion of acrAB or tolC increased fluoroquinolone susceptibility 4-fold, whereas replacement of gyrA double mutations (S83F D87N) with wild-type gyrA increased susceptibility >500-fold. These results indicate that a combination of topoisomerase gene mutations, as well as enhanced antimicrobial efflux, plays a critical role in the development of fluoroquinolone resistance in both laboratory-derived and naturally occurring quinolone-resistant serovar Typhimurium strains.

Published ahead of print on 16 October 2006.

Present address: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226.

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