PUB - Publikationen an der Universität Bielefeld

AIMS: Quinone compounds are electron carriers and have antimicrobial and toxic properties due to their mode-of-actions as electrophiles and oxidants. However, the regulatory mechanism of quinone resistance is less well understood in the pathogen Staphylococcus aureus.; RESULTS: Methylhydroquinone (MHQ) caused a thiol-specific oxidative and electrophile stress response in the S. aureus transcriptome as revealed by the induction of the PerR, QsrR, CstR, CtsR and HrcA regulons. The SACOL2531-29 operon was most strongly upregulated by MHQ and was renamed as mhqRED operon based on its homology to the Bacillus subtilis locus. Here, we characterized the MarR-type regulator MhqR (SACOL2531) as quinone-sensing repressor of the mhqRED operon, which confers quinone and antimicrobial resistance in S. aureus. The mhqRED operon responds specifically to MHQ and less pronounced to pyocyanin and ciprofloxacin, but not to ROS, HOCl or aldehydes. The MhqR repressor binds specifically to an 9-9 bp inverted repeat (MhqR operator) upstream of the mhqRED operon and is inactivated by MHQ in vitro, which does not involve a thiol-based mechanism. In phenotypic assays, the mhqR deletion mutant was resistant to MHQ and quinone-like antimicrobial compounds, including pyocyanin, ciprofloxacin, norfloxacin and rifampicin. In addition, the mhqR mutant was sensitive to sub-lethal ROS and 24 h post macrophage infections, but acquired an improved survival under lethal ROS stress and after long-term infections. Conclusion and Innovation: In conclusion, our studies provide a link between quinone and antimicrobial resistance via the MhqR regulon of S. aureus.