Oxidation sensing and quorum sensing significantly affect bacterial
physiology and host–pathogen interactions. However, little attention
has been paid to the cross-talk between these two seemingly orthogonal
signaling pathways. Herewe showthat the quorum-sensing agr
system has a built-in oxidation-sensing mechanism through an intramolecular
disulfide switch possessed by the DNA-binding domain of
the response regulator AgrA. Biochemical and mass spectrometric
analysis revealed that oxidation induces the intracellular disulfide
bond formation between Cys-199 and Cys-228, thus leading to dissociation
of AgrA fromDNA.Molecular dynamics (MD) simulations suggest
that the disulfide bond formation generates a steric clash
responsible for the abolished DNA binding of the oxidized AgrA.
Mutagenesis studies further established that Cys-199 is crucial for
oxidation sensing. The oxidation-sensing role of Cys-199 is further
supported by the observation that the mutant Staphylococcus aureus
strain expressing AgrAC199S is more susceptible to H2O2 owing to
repression of the antioxidant bsaA gene under oxidative stress. Together,
our results showthat oxidation sensing is a component of the
quorum-sensing agr signaling system, which serves as an intrinsic
checkpoint to ameliorate the oxidation burden caused by intense
metabolic activity and potential host immune response.