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Multiple clinical studies have demonstrated improved outcomes when MRSA bacteremia is treated with dual antibiotic therapy that includes a \u03b2-lactam antibiotic such as cefazolin. This is a paradox as MRSA should be inherently resistant to this class of antibiotics. We report on a serendipitous observation of a phenotype where MRSA became sensitive to cefazolin when cultured in a physiologic relevant media of fetal bovine serum as well as in synovial fluid. This could be observed across multiple clinical isolates. Expected resistance was maintained when cultured in Muller Hinton Broth (MHB). MRSA \u03b2-lactam antibiotic resistance is mediated by PBP2a, a penicillin-binding protein encoded by\n                      <jats:italic toggle=\"yes\">mecA<\/jats:italic>\n                      . We hypothesized that this phenotype of antibiotic sensitivity in physiologic medium was based, in part, on levels of PBP2a expression and post-translational modifications of peptidoglycan wall teichoic acid (WTA). We, therefore, conducted quantitative RT-PCR analysis and Western blotting which demonstrated limited\n                      <jats:italic toggle=\"yes\">mecA<\/jats:italic>\n                      expression PBP2a protein level when cultured in FBS as compared to the clinical microbiology standard MHB, respectively. Whole genome sequencing of loss of function mutants generated through serial passaging in FBS revealed that the\n                      <jats:italic toggle=\"yes\">clp<\/jats:italic>\n                      family of proteins and\n                      <jats:italic toggle=\"yes\">rpo<\/jats:italic>\n                      genes were involved in \u03b2-lactam resistance. Cell wall peptidoglycan analysis suggested that WTA glycosylation was altered between \u03b2-lactam resistant and sensitive MRSA phenotypes. Together, this suggests that\n                      <jats:italic toggle=\"yes\">clpP<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">rpoB,<\/jats:italic>\n                      and WTA glycosylation are involved with the \u03b2-lactam sensitivity phenotype in MRSA and can be new potential targets for MRSA treatment.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00396-25","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T14:02:06Z","timestamp":1770904926000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Methicillin-resistant\n                    <i>Staphylococcus aureus<\/i>\n                    has phenotypic variation in\n                    <i>mecA<\/i>\n                    expression that alters antibiotic sensitivity"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-4265-0429","authenticated-orcid":false,"given":"Dongzhu","family":"Ma","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Bethel Musculoskeletal Research Center, Department of Orthopaedic Surgery, University of Pittsburgh","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rekha","family":"Arya","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Bethel Musculoskeletal Research Center, Department of Orthopaedic Surgery, University of Pittsburgh","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beth 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