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Antimicrobial Agents and Chemotherapy, March 2009, p. 1080-1087, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.01005-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Multiple Regulatory Pathways Associated with High-Level Ciprofloxacin and Multidrug Resistance in Salmonella enterica Serovar Enteritidis: Involvement of ramA and Other Global Regulators{triangledown}

Edel O'Regan,1 Teresa Quinn,1 Jean-Marie Pagès,2 Matthew McCusker,1 Laura Piddock,3 and Séamus Fanning1*

Centres for Food Safety and Food-borne Zoonomics, UCD Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland,1 UMR-MD1, Transporteurs Membranaires, Chimiorésistance et Drug-Design, Facultés de Médecine et de Pharmacie, Université de la Méditerranée, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France,2 Antimicrobial Agents Research Group, Division of Immunity and Infection, The Medical School, University of Birmingham, Birmingham B15 2TT, United Kingdom3

Received 27 July 2008/ Returned for modification 9 October 2008/ Accepted 12 December 2008

Mechanisms of antibiotic resistance were examined in nalidixic acid-resistant Salmonella enterica serovar Enteritidis field isolates displaying decreased susceptibility to ciprofloxacin and in in vitro-derived ciprofloxacin-resistant mutants (104-cip and 5408-cip). All field isolates harbored a single gyrA mutation (D87Y). Deletion of acrB and complementation with wild-type gyrA increased quinolone susceptibility. Selection for ciprofloxacin resistance was associated with the development of an additional gyrA (S83F) mutation in 104-cip, novel gyrB (E466D) and parE (V461G) mutations in 5408-cip, overexpression of acrB and decreased susceptibility to nonquinolone antibiotics in both mutants, and decreased OmpF production and altered lipopolysaccharide in 104-cip. Complementation of mutated gyrA and gyrB with wild-type alleles restored susceptibility to quinolones in 104-cip and significantly decreased the ciprofloxacin MIC in 5408-cip. Complementation of parE had no effect on quinolone MICs. Deletion of acrB restored susceptibility to ciprofloxacin and other antibiotics tested. Both soxS and marA were overexpressed in 104-cip, and ramA was overexpressed in 5408-cip. Inactivation of each of these global regulators lowered ciprofloxacin MICs, decreased expression of acrB, and restored susceptibility to other antibiotics. Mutations were found in soxR (R20H) and in soxS (E52K) in 104-cip and in ramR (G25A) in 5408-cip. In conclusion, both efflux activity and a single gyrA mutation contribute to nalidixic acid resistance and reduced ciprofloxacin sensitivity. Ciprofloxacin resistance and decreased susceptibility to multiple antibiotics can result from different genetic events leading to development of target gene mutations, increased efflux activity resulting from differential expression of global regulators associated with mutations in their regulatory genes, and possible altered membrane permeability.

* Corresponding author. Mailing address: Centres for Food Safety and Food-borne Zoonomics, UCD Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland. Phone: (353-1) 716 6082. Fax: (353-1) 716 6091. E-mail: sfanning{at}ucd.ie

{triangledown} Published ahead of print on 22 December 2008.

Antimicrobial Agents and Chemotherapy, March 2009, p. 1080-1087, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.01005-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kehrenberg, C., Cloeckaert, A., Klein, G., Schwarz, S. (2009). Decreased fluoroquinolone susceptibility in mutants of Salmonella serovars other than Typhimurium: detection of novel mutations involved in modulated expression of ramA and soxS. J Antimicrob Chemother 64: 1175-1180 [Abstract] [Full Text]  


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