Defects in anaplerotic metabolism sensitize <i>Staphylococcus aureus</i> small colony variants to bicarbonate

<i>Staphylococcus aureus</i> is one of the major bacterial contributors to human deaths around the world. Metabolic flexibility allows <i>S. aureus</i> to alter energy generation and resist oxidative and antibiotic killing, facilitating persistence in the host. Bicarbonate has been used for over a century for cleaning and hygiene without completely understanding its antimicrobial properties. We report that small colony variants (SCVs) are defective for bicarbonate anaplerotic metabolism, which is required to detoxify bicarbonate. As a result, bicarbonate inhibits the growth of SCVs by alkalinizing the cytoplasm. Cytoplasmic alkalinization also resensitizes SCVs to aminoglycoside killing, implicating bicarbonate as an effective antimicrobial adjuvant for treating glycolytic <i>S. aureus</i>. Our study defines the impacts of bicarbonate on the growth of SCVs and the metabolic pathways involved in detoxification, indicating that bicarbonate could be effective at controlling chronic <i>S. aureus</i> infections.