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However, very little is known about the mechanisms by which\n              <jats:italic>S. aureus<\/jats:italic>\n              dominantly colonizes and causes severe disease in DFUs. Herein, we utilized a pressure wound model in diabetic TALLYHO\/JngJ mice to reproduce ischemic hypoxic tissue damage seen in DFUs and demonstrated that anaerobic fermentative growth of\n              <jats:italic>S. aureus<\/jats:italic>\n              significantly increased the virulence and the severity of disease by activating two-component regulatory systems leading to expression of virulence factors. Our\n              <jats:italic>in vitro<\/jats:italic>\n              studies showed that supplementation of nitrate as a terminal electron acceptor promotes anaerobic respiration and suppresses the expression of\n              <jats:italic>S. aureus<\/jats:italic>\n              virulence factors through inactivation of two-component regulatory systems, suggesting potential therapeutic benefits by promoting anaerobic nitrate respiration. Our\n              <jats:italic>in vivo<\/jats:italic>\n              studies revealed that dietary supplementation of L-arginine (L-Arg) significantly attenuated the severity of disease caused by\n              <jats:italic>S. aureus<\/jats:italic>\n              in the pressure wound model by providing nitrate. Collectively, these findings highlight the importance of anaerobic fermentative growth in\n              <jats:italic>S. aureus<\/jats:italic>\n              pathogenesis and the potential of dietary L-Arg supplementation as a therapeutic to prevent severe\n              <jats:italic>S. aureus<\/jats:italic>\n              infection in DFUs.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                <jats:italic>S. aureus<\/jats:italic>\n                is the most common cause of infection in DFUs, often resulting in lower-extremity amputation with a distressingly poor 5-year survival rate. Treatment for\n                <jats:italic>S. aureus<\/jats:italic>\n                infections has largely remained unchanged for decades and involves tissue debridement with antibiotic therapy. With high levels of conservative treatment failure, recurrence of ulcers, and antibiotic resistance, a new approach is necessary to prevent lower-extremity amputations. Nutritional aspects of DFU treatment have largely been overlooked as there has been contradictory clinical trial evidence, but very few\n                <jats:italic>in vitro<\/jats:italic>\n                and\n                <jats:italic>in vivo<\/jats:italic>\n                modelings of nutritional treatment studies have been performed. Here we demonstrate that dietary supplementation of L-Arg in a diabetic mouse model significantly reduced duration and severity of disease caused by\n                <jats:italic>S. aureus<\/jats:italic>\n                . These findings suggest that L-Arg supplementation could be useful as a potential preventive measure against severe\n                <jats:italic>S. aureus<\/jats:italic>\n                infections in DFUs.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/msphere.00774-23","type":"journal-article","created":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T14:00:32Z","timestamp":1709301632000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":6,"title":["L-arginine supplementation abrogates hypoxia-induced virulence of\n            <i>Staphylococcus aureus<\/i>\n            in a murine diabetic pressure wound model"],"prefix":"10.1128","volume":"9","author":[{"given":"Carol L.","family":"Baker","sequence":"first","affiliation":[{"name":"Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi, 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