Staphylococcus aureus adapts to the host nutritional environment by coordinating the activity of central metabolic enzymes.

The nutritional demands imposed by disparate infection sites represent a significant barrier to bacterial survival. Yet, the proclivity of pathogens such as Staphylococcus aureus to cause disease at nearly all host sites implies significant metabolic flexibility to promote infection. S. aureus catabolizes glucose in several ways, including the phosphotransacetylase (Pta) - acetate kinase (AckA) pathway. The Pta-AckA pathway uses acetyl-CoA derived from the major glycolytic end-product, pyruvate, to rapidly generate ATP, producing acetate as a byproduct. Yet, flux through Pta-AckA necessitates coordinating glycolytic activity with the production of acetyl-CoA and its delivery to Pta-AckA. The generation of acetyl-CoA occurs through the pyruvate dehydrogenase (PDH) complex, an enzyme that requires attachment of the metabolic cofactor, lipoic acid, for its function. Thus, delivery of lipoic acid to enzyme complexes has the potential to serve as a determinant of metabolic adaptation. Here, we provide evidence for a functional link between the lipoic acid transfer enzyme, LipL, and Pta. We demonstrate pta and lipL are transcriptionally coupled and that Pta and LipL directly interact, with potential to direct metabolic flux through Pta-AckA. Both Δpta and ΔlipL mutants are defective for acetate production with evidence for alternative fates for pyruvate that depend on blockade upstream or downstream of the pyruvate node. The functional pairing of Pta and LipL is required for optimal skin infection, whereas Pta and LipL have separable functions in bloodstream infection. Furthermore, we found that a complete block to acetate production leads to significant attenuation in vivo, cementing a direct role for acetogenesis in infection. Together, our results establish a mechanism by which S. aureus regulates metabolite flux by coupling enzymes in linked metabolic pathways to promote energy balance and survival during infection.