Staphylococcus aureus metabolic strategies to survive nitrosative stress

Staphylococcus aureus is a major cause of severe infections caused by strains that are antibiotic resistant. In the nasopharynx, S. aureus thrives with high concentrations of nitric oxide (NO•) and reactive nitrogen species (RNS), which are responsible for the nitrosylation of several cellular life support enzymes, including the respiratory electron transfer proteins. The capacity of S. aureus to maintain metabolic and redox homeostasis in this environment is essential for virulence. In this work, we show that S. aureus is able to resist the stress caused by the nitric oxide donors, spermine NONOate and GSNO, when using galactose, an abundant carbon source present in the nasopharynx. Our data reveal that NO• induces a distinct metabolism by stimulating the production of reducing power (NADPH) for biosynthetic processes, namely amino acid biosynthesis. Furthermore, S. aureus α-acetolactate synthase (ALS) enzyme is shown to prevent intracellular acidification promoted by NO•, by producing α-acetolactate for the synthesis of branched-chain amino acids (BCAAs) and activating the TCA cycle. Importantly, ALS contributes to the successful infection of NO•-producing murine macrophages.