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Antimicrobial Agents and Chemotherapy, March 2009, p. 903-911, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.01287-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Identification by Genomic and Genetic Analysis of Two New Genes Playing a Key Role in Intermediate Glycopeptide Resistance in Staphylococcus aureus{triangledown}

Adriana Renzoni,1,{dagger} William L. Kelley,1,{dagger} Christine Barras,1 Antoinette Monod,1 Elzbieta Huggler,1 Patrice François,2 Jacques Schrenzel,2,3 René Studer,3 Pierre Vaudaux,1* and Daniel P. Lew1

Service of Infectious Diseases,1 Genomic Research Laboratory,2 Clinical Bacteriology Laboratory, Geneva University Hospital, Geneva CH-1211 14, Switzerland3

Received 25 September 2008/ Returned for modification 26 November 2008/ Accepted 17 December 2008

Endogenous, low-level glycopeptide resistance in Staphylococcus aureus results from multifactorial genetic changes. Comparative genomic hybridization analysis revealed the specific deletion of a 1.8-kb segment encompassing two adjacent open reading frames (ORFs) of unknown function in a teicoplanin-susceptible revertant (strain 14-4rev) compared to the sequence of its isogenic, teicoplanin-resistant parental strain, strain 14-4. This provocative finding prompted us to perform a detailed genetic analysis of the contribution of this genomic segment to glycopeptide resistance. Despite repeated efforts in our laboratory, 14-4 and 14-4rev have proven refractory to most genetic manipulations. To circumvent this difficulty, we evaluated the contribution of both putative ORFs (designated teicoplanin resistance factors trfA and trfB) on teicoplanin resistance in a different, genetically tractable background. Genetic analysis showed that single or double trfA and/or trfB mutations abolished teicoplanin resistance in two independent teicoplanin-resistant derivatives of NCTC8325 strain ISP794 generated by two-step passages with the drug. The frequency of teicoplanin-resistant mutants was markedly decreased by the absence of trfAB in the teicoplanin-susceptible ISP794 background. Nevertheless, a low rate of teicoplanin-resistant mutants was selected from ISP794 trfAB, thus indicating an additional contribution of trfAB-independent pathways in the emergence of low-level glycopeptide resistance. Further experiments performed with clinical glycopeptide-intermediate S. aureus isolate NRS3 indicated that the trfAB mutation could affect not only teicoplanin resistance but also vancomycin and oxacillin resistance. In conclusion, our study demonstrates the key role of two novel loci in endogenous, low-level glycopeptide resistance in S. aureus whose precise molecular functions warrant further investigation.

* Corresponding author. Mailing address: Service of Infectious Diseases, Geneva University Hospital, 24 rue Micheli-du-Crest, Geneva CH-1211 14, Switzerland. Phone: (4122) 3729826. Fax: (4122) 3729830. E-mail: Pierre.Vaudaux{at}hcuge.ch

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

{dagger} Both of these authors contributed equally to this work.

Antimicrobial Agents and Chemotherapy, March 2009, p. 903-911, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.01287-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kato, Y., Suzuki, T., Ida, T., Maebashi, K. (2009). Genetic changes associated with glycopeptide resistance in Staphylococcus aureus: predominance of amino acid substitutions in YvqF/VraSR. J Antimicrob Chemother 0: dkp394v1-dkp394 [Abstract] [Full Text]  


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