Increased flexibility in the use of exogenous lipoic acid by Staphylococcus aureus

Lipoic acid is a cofactor required for intermediary metabolism that is either synthesized de novo or acquired from environmental sources. The bacterial pathogen Staphylococcus aureus encodes enzymes required for de novo biosynthesis, but also encodes two ligases, LplA1 and LplA2, that are sufficient for lipoic acid salvage during infection. S. aureus also encodes two H proteins, GcvH of the glycine cleavage system and the homologous GcvH‐L encoded in an operon with LplA2. GcvH is a recognized conduit for lipoyl transfer to α‐ketoacid dehydrogenase E2 subunits, while the function of GcvH‐L remains unclear. The potential to produce two ligases and two H proteins is an unusual characteristic of S. aureus that is unlike most other Gram positive Firmicutes and might allude to an expanded pathway of lipoic acid acquisition in this microorganism. Here, we demonstrate that LplA1 and LplA2 facilitate lipoic acid salvage by differentially targeting lipoyl domain‐containing proteins; LplA1 targets H proteins and LplA2 targets α‐ketoacid dehydrogenase E2 subunits. Furthermore, GcvH and GcvH‐L both facilitate lipoyl relay to E2 subunits. Altogether, these studies identify an expanded mode of lipoic acid salvage used by S. aureus and more broadly underscore the importance of bacterial adaptations when faced with nutritional limitation.