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Antimicrobial Agents and Chemotherapy, February 2004, p. 546-555, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.546-555.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Subinhibitory Concentrations of Linezolid Reduce Staphylococcus aureus Virulence Factor Expression

Katussevani Bernardo,1,{dagger} Norbert Pakulat,1,{dagger} Silke Fleer,1 Annabelle Schnaith,1 Olaf Utermöhlen,1,2 Oleg Krut,1 Stefan Müller,2 and Martin Krönke1,2*

Institute for Medical Microbiology, Immunology, and Hygiene, Medical Center,1 Center for Molecular Medicine, University of Cologne, Cologne, Germany2

Received 15 July 2003/ Returned for modification 24 August 2003/ Accepted 30 October 2003

The influence of the antibiotic linezolid on the secretion of exotoxins by Staphylococcus aureus was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis combined with matrix-assisted laser desorption ionization-time of flight mass spectrometry and Western blot analysis. S. aureus suspensions were treated with grading subinhibitory concentrations of linezolid (12.5, 25, 50, and 90% of MIC) at different stages of bacterial growth (i.e., an optical density at 540 nm [OD540] of 0.05 or 0.8). When added to S. aureus cultures at an OD540 of 0.05, linezolid reduced in a dose-dependent manner the secretion of specific virulence factors, including staphylococcal enterotoxin A (SEA) and SEB, bifunctional autolysin, autolysin, protein A, and alpha- and beta-hemolysins. In contrast, other presumably nontoxic exoproteins remained unchanged or even accumulated in supernatants in the presence of linezolid at a 90% MIC. Similarily, when added at OD540 of 0.8, that is, after quorum sensing, linezolid reduced the release of virulence factors, whereas the relative abundance of nontoxic exoproteins such as triacylglycerol lipase, glycerol ester hydrolase, DnaK, or translation elongation factor EF-Tu was found to be increased. Consistently, linezolid reduced in a dose-dependent manner the tumor necrosis factor-inducing activity secreted by S. aureus into the culture supernatants. The results of our study suggest that the expression of virulence factors in S. aureus is especially sensitive to the inhibition of protein synthesis by linezolid, which should be an advantage in the treatment of infections with toxin-producing S. aureus.

* Corresponding author. Mailing address: Institute for Medical Microbiology, Immunology, and Hygiene, Medical Center, University of Cologne, Goldenfelsstr. 19-21, 50935 Cologne, Germany. Phone: 49-221-478-3060. Fax: 49-221-478-3067. E-mail: martin.kroenke{at}medizin.uni-koeln.de.

{dagger} K.B. and N.P. contributed equally to this study.

Antimicrobial Agents and Chemotherapy, February 2004, p. 546-555, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.546-555.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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