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Antimicrobial Agents and Chemotherapy, June 2009, p. 2298-2305, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01016-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Genetic Analysis of Colistin Resistance in Salmonella enterica Serovar Typhimurium{triangledown} ,{dagger}

Song Sun,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 29 July 2008/ Returned for modification 29 September 2008/ Accepted 23 March 2009

Colistin is a cyclic cationic peptide that kills gram-negative bacteria by interacting with and disrupting the outer membrane. We isolated 44 independent mutants in Salmonella enterica serovar Typhimurium with reduced susceptibility to colistin and identified 27 different missense mutations located in the pmrA and pmrB genes (encoding the regulator and sensor of a two-component regulatory system) that conferred increased resistance. By comparison of the two homologous sensor kinases, PmrB and EnvZ, the 22 missense mutations identified in pmrB were shown to be located in four different structural domains of the protein. All five pmrA mutations were located in the phosphate receiver domain of the regulator protein. The mutants appeared at a mutation rate of 0.6 x 10–6 per cell per generation. The MICs of colistin for the mutants increased 2- to 35-fold, and the extent of killing was reduced several orders of magnitude compared to the susceptible strain. The growth rates of the mutants were slightly reduced in both rich medium and M9-glycerol minimal medium, whereas growth in mice appeared unaffected by the pmrA and pmrB mutations. The low fitness costs and the high mutation rate suggest that mutants with reduced susceptibility to colistin could emerge in clinical settings.

* Corresponding author. Mailing address: Uppsala University, 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 30 March 2009.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, June 2009, p. 2298-2305, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01016-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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