| Summary: | <i>Staphylococcus aureus</i> (<i>S. aureus</i>) is an aggressive opportunistic pathogen of prominent virulence and antibiotic resistance. These characteristics are due in part to the accessory gene regulator (<i>agr</i>) quorum-sensing system, which allows for the rapid adaptation of <i>S. aureus</i> to environmental changes and thus promotes virulence and the development of pathogenesis. AgrA is the <i>agr</i> system response regulator that binds to the P2 and P3 promoters and upregulates <i>agr</i> expression. In this study, we reveal that <i>S. aureus</i> AgrA is modified by covalent binding of CoA (CoAlation) in response to oxidative or metabolic stress. The sites of CoAlation were mapped by liquid chromatography tandem mass spectrometry (LC–MS/MS) and revealed that oxidation-sensing Cys199 is modified by CoA. Surface plasmon resonance (SPR) analysis showed an inhibitory effect of CoAlation on the DNA-binding activity, as CoAlated AgrA had significantly lower affinity towards the P2 and P3 promoters than non-CoAlated AgrA. Overall, this study provides novel insights into the mode of transcriptional regulation in <i>S. aureus</i> and further elucidates the link between the quorum-sensing and oxidation-sensing roles of the <i>agr</i> system.
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