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SCVs lack a proton motive force (PMF), increasing antibiotic tolerance and contributing to persistent infection in the host. Bicarbonate is an abundant antimicrobial compound in the human host that\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      encounters during infection. Bicarbonate alters the PMF, enhancing antibiotic susceptibility in\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      , but its impact on\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      SCVs remains unexplored. We report that bicarbonate inhibits the growth of\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      SCVs at concentrations that do not affect\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      wild type, due to defective bicarbonate anaplerotic metabolism, resulting in increased cytoplasmic pH and alkaline toxicity. Inactivation of pyruvate carboxylase (Pyc), a critical enzyme in bicarbonate anaplerotic metabolism that combines bicarbonate and pyruvate to form oxaloacetate, increases bicarbonate sensitivity in\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      , indicating that bicarbonate anaplerotic metabolism plays a vital role in bicarbonate detoxification. While SCVs upregulate Pyc in response to bicarbonate, cellular pyruvate levels are insufficient to sustain bicarbonate anaplerotic metabolism. Exogenous pyruvate restores bicarbonate anaplerotic metabolism and lowers the cytoplasmic pH, protecting SCVs from bicarbonate toxicity. Cytoplasmic pH alterations by bicarbonate also resensitize SCVs to aminoglycosides.\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      treated with bicarbonate is more susceptible to neutrophil killing, indicating that bicarbonate decreases the virulence of\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      . This study identifies bicarbonate anaplerotic metabolism as a\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      detoxification mechanism for bicarbonate toxicity and demonstrates that modulating anaplerotic metabolism may be an effective treatment for\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      infections.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                      is one of the major bacterial contributors to human deaths around the world. Metabolic flexibility allows\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      . 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\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      infections.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.01685-25","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T14:19:03Z","timestamp":1758118743000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Defects in anaplerotic metabolism sensitize\n                    <i>Staphylococcus aureus<\/i>\n                    small colony variants to bicarbonate"],"prefix":"10.1128","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4385-1537","authenticated-orcid":false,"given":"Asif","family":"Iqbal","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05ect4e57","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathobiological Sciences, Louisiana State University and Agricultural and Mechanical College, School of Veterinary Medicine","place":["Baton Rouge, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zannatul H.","family":"Tumpa","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05ect4e57","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathobiological Sciences, Louisiana State University and Agricultural and Mechanical College, School of Veterinary Medicine","place":["Baton Rouge, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wyatt 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