{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T21:25:54Z","timestamp":1793049954973,"version":"4.5.0"},"reference-count":50,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T00:00:00Z","timestamp":1738281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T00:00:00Z","timestamp":1738281600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["RO1AI119380-06"],"award-info":[{"award-number":["RO1AI119380-06"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["P30-GM14593"],"award-info":[{"award-number":["P30-GM14593"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Texas Hip and Knee Center"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Infect Immun"],"published-print":{"date-parts":[[2025,1,31]]},"abstract":"ABSTRACT<\/jats:title>\n \n \n \n We demonstrate that mutation of the staphylococcal accessory regulator A (\n sarA<\/jats:italic>\n ) in the USA300 strain LAC limits virulence in a murine osteomyelitis model to a greater extent than mutation of the accessory gene regulator (\n agr<\/jats:italic>\n ) and that it does so irrespective of the functional status of\n agr<\/jats:italic>\n . Protease production was decreased in the\n agr<\/jats:italic>\n mutant but increased in\n sarA<\/jats:italic>\n and\n sarA\/agr<\/jats:italic>\n mutants to a degree that limited biofilm formation. Extracellular protein A (eSpa) and full-length extracellular nuclease (Nuc1) were absent in the conditioned medium (CM) from\n sarA<\/jats:italic>\n and\n sarA<\/jats:italic>\n \/\n agr<\/jats:italic>\n mutants, and their abundance was restored in both mutants by eliminating protease production. Cytotoxicity of CM for osteoblasts and osteoclasts was also reduced in both mutants. Cytotoxicity was restored in a protease-deficient\n sarA<\/jats:italic>\n mutant but not in the protease-deficient\n sarA<\/jats:italic>\n \/\n agr<\/jats:italic>\n mutant. Reduced cytotoxicity was correlated with the reduced abundance of full-length \u03b1-toxin, LukF, and LukS in\n sarA<\/jats:italic>\n and\n sarA<\/jats:italic>\n \/\n agr<\/jats:italic>\n mutants. The abundance of these toxins in their full-length form was increased in the protease-deficient\n sarA<\/jats:italic>\n mutant by comparison to LAC, demonstrating that mutation of\n sarA<\/jats:italic>\n increases the production of these toxins but increased protease production limits their abundance in full-length and presumably functional forms. Most importantly, eliminating protease production enhanced the virulence of\n sarA<\/jats:italic>\n and\n sarA\/agr<\/jats:italic>\n mutants, but had no impact in the\n agr<\/jats:italic>\n mutant. We conclude that a key factor in the attenuation of LAC\n sarA<\/jats:italic>\n and\n sarA<\/jats:italic>\n \/\n agr<\/jats:italic>\n mutants in osteomyelitis is the increased production of extracellular proteases and its impact on virulence factors that contribute to biofilm formation and cytotoxicity.\n <\/jats:p>\n \n \n IMPORTANCE<\/jats:bold>\n <\/jats:title>\n \n The persistent emergence of antibiotic-resistant strains has rekindled interest in anti-virulence strategies to combat\n S. aureus<\/jats:italic>\n infections. Numerous reports describe anti-virulence strategies focusing on key regulatory elements that globally influence virulence factor production, the two most commonly targeted being the accessory gene regulator (\n agr<\/jats:italic>\n ) and the staphylococcal accessory regulator A (\n sarA<\/jats:italic>\n ). We demonstrate that mutation of\n sarA<\/jats:italic>\n limits virulence to a greater extent than mutation of\n agr<\/jats:italic>\n and that this can be attributed to increased protease production in both\n sarA<\/jats:italic>\n and\n sarA<\/jats:italic>\n \/\n agr<\/jats:italic>\n mutants. This illustrates the critical role of\n sarA<\/jats:italic>\n in protease-mediated post-translational regulation in\n S. aureus<\/jats:italic>\n . It also suggests that an inhibitor of\n sarA<\/jats:italic>\n would be more effective than an inhibitor of\n agr<\/jats:italic>\n in overcoming the therapeutic recalcitrance of osteomyelitis and that such an inhibitor would remain effective even in the context of\n agr<\/jats:italic>\n mutants known to arise\n in vivo<\/jats:italic>\n during the transition from acute to chronic infection.\n <\/jats:p>\n <\/jats:sec>\n <\/jats:sec>","DOI":"10.1128\/iai.00473-24","type":"journal-article","created":{"date-parts":[[2024,11,29]],"date-time":"2024-11-29T14:00:17Z","timestamp":1732888817000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":16,"title":["The ability of\n sarA<\/i>\n to limit protease production plays a key role in the pathogenesis of\n Staphylococcus aureus<\/i>\n osteomyelitis irrespective of the functional status of\n 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