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Antimicrobial Agents and Chemotherapy, May 2008, p. 1737-1742, Vol. 52, No. 5
0066-4804/08/$08.00+0     doi:10.1128/AAC.01015-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Linezolid and Tiamulin Cross-Resistance in Staphylococcus aureus Mediated by Point Mutations in the Peptidyl Transferase Center {triangledown}

Keith Miller,1 Colin J. Dunsmore,2 Colin W. G. Fishwick,2 and Ian Chopra1*

Antimicrobial Research Centre and Institute of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom,1 Antimicrobial Research Centre and School of Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom2

Received 2 August 2007/ Returned for modification 14 December 2007/ Accepted 26 December 2007

Oxazolidinone and pleuromutilin antibiotics are currently used in the treatment of staphylococcal infections. Although both antibiotics inhibit protein synthesis and have overlapping binding regions on 23S rRNA, the potential for cross-resistance between the two classes through target site mutations has not been thoroughly examined. Mutants of Staphylococcus aureus resistant to linezolid were selected and found to exhibit cross-resistance to tiamulin, a member of the pleuromutilin class of antibiotics. However, resistance was unidirectional because mutants of S. aureus selected for resistance to tiamulin did not exhibit cross-resistance to linezolid. This contrasts with the recently described PhLOPSA phenotype, which confers resistance to both oxazolidinones and pleuromutilins. The genotypes responsible for the phenotypes we observed were examined. Selection with tiamulin resulted in recovery of mutants with changes in the single-copy rplC gene (Gly155Arg, Ser158Leu, or Arg149Ser), whereas selection with linezolid led to recovery of mutants with changes (G2576U in 23S rRNA) in all five copies of the multicopy operon rrn. In contrast, cross-resistance to linezolid was exhibited by tiamulin-resistant mutants generated in a single-copy rrn knockout strains of Escherichia coli, illustrating that the copy number of 23S rRNA is the limiting factor in the selection of 23S rRNA tiamulin-resistant mutants. The interactions of linezolid and tiamulin with the ribosome were modeled to seek explanations for resistance to both classes in the 23S rRNA mutants and the lack of cross-resistance between tiamulin and linezolid following mutation in rplC.

* Corresponding author. Mailing address: Antimicrobial Research Centre and Institute of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom. Phone: 44 113 233 5604. Fax: 44 113 233 1407. E-mail: i.chopra{at}leeds.ac.uk

{triangledown} Published ahead of print on 7 January 2008.

Antimicrobial Agents and Chemotherapy, May 2008, p. 1737-1742, Vol. 52, No. 5
0066-4804/08/$08.00+0     doi:10.1128/AAC.01015-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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