ABSTRACT In Staphylococcus aureus , the sigB operon codes for the alternative sigma factor σ ^B and its regulators that enable the bacteria to rapidly respond to environmental stresses via redirection of transcriptional priorities. However, a full model of σ ^B regulation in S. aureus has not yet emerged. Earlier data has suggested that mazEF , a toxin-antitoxin (TA) module immediately upstream of the sigB operon, was transcribed with the sigB operon. Here we demonstrate that the promoter P _mazE upstream of mazEF is essential for full σ ^B activity and that instead of utilizing autorepression typical of TA systems, sigB downregulates this promoter, providing a negative-feedback loop for sigB to repress its own transcription. We have also found that the transcriptional regulator SarA binds and activates P _mazE . In addition, P _mazE was shown to respond to environmental and antibiotic stresses in a way that provides an additional layer of control over sigB expression. The antibiotic response also appears to occur in two other TA systems in S. aureus , indicating a shared mechanism of regulation.