Staphylococcus aureus exploits lipoic acid salvage to combat host oxidative stress.

Phagocytic leukocytes employ reactive oxygen species to defend against pathogenic microorganisms. The bacterial pathogen Staphylococcus aureus adapts to oxidative stress by producing antioxidant enzymes and small molecules to protect proteins, nucleic acids, and other essential cellular components. Here, we show that the lipoic acid carrier protein GcvH-L promotes S. aureus resistance to oxidative stress. The gene encoding GcvH-L lies within a conserved operon in several pathogenic microorganisms. The operon also encodes LplA2, a redox-responsive lipoyl ligase, and SirTM, an ADP-ribosyltransferase. We demonstrate that ADP-ribosylation of lipoyl-GcvH-L protects lipoic acid from oxidation and regulates its transfer from GcvH-L to enzyme complexes needed for central metabolism. A ΔgcvH-L mutant is attenuated during infection and is more sensitive to phagocyte respiratory burst, phenotypes that are abrogated in NADPH oxidase-deficient mice. Thus, ADP-ribosylation and lipoylation converge on GcvH-L to promote S. aureus resistance to oxidative stress.