title: Global analysis of the impact of linezolid onto virulence factor production in S. aureus USA300.
abstract: The translation inhibitor linezolid is an antibiotic of last resort against Gram-positive pathogens including methicillin resistant strains of the nosocomial pathogen Staphylococcus aureus. Linezolid is reported to inhibit production of extracellular virulence factors, but the molecular cause is unknown. To elucidate the physiological response of S. aureus to linezolid in general and the inhibition of virulence factor synthesis in particular a holistic study was performed. Linezolid was added to exponentially growing S. aureus cells and the linezolid stress response was analyzed with transcriptomics and quantitative proteomics methods. In addition, scanning and transmission electron microscopy experiments as well as fluorescence microscopy analyses of the cellular DNA and membrane were performed. As previously observed in studies on other translation inhibitors, S. aureus adapts its protein biosynthesis machinery to the reduced translation efficiency. For example the synthesis of ribosomal proteins was induced. Also unexpected results like a decline in the amount of extracellular and membrane proteins were obtained. In addition, cell shape and size changed after linezolid stress and cell division was diminished. Finally, the chromosome was condensed after linezolid stress and lost contact to the membrane. These morphological changes cannot be explained by established theories. A new hypothesis is discussed, which suggests that the reduced amount of membrane and extracellular proteins and observed defects in cell division are due to the disintegration of transertion complexes by linezolid.
authors.affiliation: Institute for Microbiology, Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Strasse 15, 17487 Greifswald, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Bonn
authors.affiliation: Institute for Microbiology, Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Strasse 15, 17487 Greifswald, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Pané-Farré
authors.affiliation: Institute for Microbiology, Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Strasse 15, 17487 Greifswald, Germany.
authors.forename: Rabea
authors.initials: R
authors.lastname: Schlüter
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Friedrich-Ludwig-Jahn-Strasse 15a, 17475 Greifswald, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Schaffer
authors.affiliation: Institute for Microbiology, Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Strasse 15, 17487 Greifswald, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Fuchs
authors.affiliation: Institute for Microbiology, Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Strasse 15, 17487 Greifswald, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Bernhardt
authors.affiliation: Institute for Microbiology, Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Strasse 15, 17487 Greifswald, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Riedel
authors.affiliation: Institute for Microbiology, Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Strasse 15, 17487 Greifswald, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Otto
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Friedrich-Ludwig-Jahn-Strasse 15a, 17475 Greifswald, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Völker
authors.affiliation: Department of Medical Microbiology, University of Groningen, Hanzeplein, 19713 GZ Groningen, Netherlands.
authors.forename: Jan Maarten
authors.initials: JM
authors.lastname: van Dijl
authors.affiliation: Institute for Microbiology, Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Strasse 15, 17487 Greifswald, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hecker
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Friedrich-Ludwig-Jahn-Strasse 15a, 17475 Greifswald, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mäder
authors.affiliation: Institute for Microbiology, Ernst-Moritz-Arndt University Greifswald, Friedrich-Ludwig-Jahn-Strasse 15, 17487 Greifswald, Germany. Electronic address: dbecher@uni-greifswald.de.
authors.forename: Dörte
authors.initials: D
authors.lastname: Becher
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000096:biosynthesis*; D004269:DNA, Bacterial / Q000235:genetics; D000069349:Linezolid / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D020411:Oligonucleotide Array Sequence Analysis; D040901:Proteomics; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism; D059467:Transcriptome; D037521:Virulence Factors / Q000096:biosynthesis*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D037521:Virulence Factors; D000069349:Linezolid
keywords: Cell division; Mechanism of action; Protein translocation; Transertion; Translation inhibition