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In line with the key role of methionine in protein biosynthesis initiation and many cellular processes most microorganisms have evolved mechanisms to synthesize methionine  de novo . Here we demonstrate that, in the bacterial pathogen  Staphylococcus aureus , a rare combination of stringent response-controlled CodY activity, T-box riboswitch and mRNA decay mechanisms regulate the synthesis and stability of methionine biosynthesis  metICFE-mdh  mRNA. In contrast to other  Bacillales  which employ S-box riboswitches to control methionine biosynthesis, the  S. aureus metICFE-mdh  mRNA is preceded by a 5′-untranslated  met  leader RNA harboring a T-box riboswitch. Interestingly, this T-box riboswitch is revealed to specifically interact with uncharged initiator formylmethionyl-tRNA (tRNA i   fMet ) while binding of elongator tRNA Met  proved to be weak, suggesting a putative additional function of the system in translation initiation control.  met  leader RNA/ metICFE-mdh  operon expression is under the control of the repressor CodY which binds upstream of the  met  leader RNA promoter. As part of the metabolic emergency circuit of the stringent response, methionine depletion activates RelA-dependent (p)ppGpp alarmone synthesis, releasing CodY from its binding site and thereby activating the  met  leader promoter. Our data further suggest that subsequent steps in  metICFE-mdh  transcription are tightly controlled by the 5′  met  leader-associated T-box riboswitch which mediates premature transcription termination when methionine is present. If methionine supply is limited, and hence tRNA i   fMet  becomes uncharged, full-length  met  leader/ metICFE-mdh  mRNA is transcribed which is rapidly degraded by nucleases involving RNase J2. Together, the data demonstrate that staphylococci have evolved special mechanisms to prevent the accumulation of excess methionine. We hypothesize that this strict control might reflect the limited metabolic capacities of staphylococci to reuse methionine as, other than  Bacillus , staphylococci lack both the methionine salvage and polyamine synthesis pathways. Thus, methionine metabolism might represent a metabolic Achilles' heel making the pathway an interesting target for future anti-staphylococcal drug development.

Methionine Biosynthesis in Staphylococcus aureus Is Tightly Controlled by a Hierarchical Network Involving an Initiator tRNA-Specific T-box Riboswitch