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Antimicrobial Agents and Chemotherapy, August 2008, p. 2734-2741, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.00205-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Mechanism and Fitness Costs of PR-39 Resistance in Salmonella enterica Serovar Typhimurium LT2 {triangledown}

Maria Pränting,1 Aurel Negrea,2 Mikael Rhen,2 and Dan I. Andersson1*

Department of Medical Biochemistry and Microbiology, Uppsala University, S-751 23 Uppsala, Sweden,1 Microbiology and Tumor Biology Centre, Karolinska Institute, S-171 82 Solna, Sweden2

Received 13 February 2008/ Returned for modification 15 April 2008/ Accepted 22 May 2008

PR-39 is a porcine antimicrobial peptide that kills bacteria with a mechanism that does not involve cell lysis. Here, we demonstrate that Salmonella enterica serovar Typhimurium can rapidly acquire mutations that reduce susceptibility to PR-39. Resistant mutants appeared at a rate of 0.4 x 10–6 per cell per generation. These mutants were about four times more resistant than the wild type and showed a greatly reduced rate of killing. Genetic analysis revealed mutations in the putative transport protein SbmA as being responsible for the observed resistance. These sbmA mutants were as fit as the wild-type parental strain as measured by growth rates in culture medium and mice and by long-term survival in stationary phase. These results suggest that resistance to certain antimicrobial peptides can rapidly develop without an obvious fitness cost for the bacteria and that resistance development could become a threat to the efficacy of antimicrobial peptides if used in a clinical setting.

* Corresponding author. Mailing address: Uppsala University, Department of Bacteriology, BMC, Box 582, IMBIM, Uppsala 75123, Sweden. Phone: 46 18 4714175. Fax: 46 18 4714673. E-mail: dan.andersson{at}imbim.uu.se

{triangledown} Published ahead of print on 2 June 2008.

Antimicrobial Agents and Chemotherapy, August 2008, p. 2734-2741, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.00205-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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