{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T13:40:12Z","timestamp":1792676412563,"version":"4.5.0"},"reference-count":24,"publisher":"American Society for Microbiology","license":[{"start":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:00:00Z","timestamp":1792627200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:00:00Z","timestamp":1792627200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Pujiang Talent Project","award":["24PJD007"],"award-info":[{"award-number":["24PJD007"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82204467"],"award-info":[{"award-number":["82204467"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanghai Municipal Hospital Development Center","award":["SHDC12020106"],"award-info":[{"award-number":["SHDC12020106"]}]},{"name":"Shanghai Municipal Health Commission","award":["20224Y0378"],"award-info":[{"award-number":["20224Y0378"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Borderline oxacillin-resistant\n                      <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                      (BORSA) represents a\n                      <jats:italic toggle=\"yes\">mecA<\/jats:italic>\n                      \/\n                      <jats:italic toggle=\"yes\">mecC<\/jats:italic>\n                      -negative phenotype characterized by oxacillin minimum inhibitory concentrations (MICs) of 1\u20138 mg\/L. The molecular basis of this resistance, particularly regarding lineage-associated differences in induction profiles, remains incompletely understood. In this study, 11 clinical BORSA isolates from pneumonia and bloodstream infections were identified among 374 clinical\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      isolates. Resistance-associated features were investigated using phenotypic profiling, whole-genome sequencing (WGS), RT-qPCR of\n                      <jats:italic toggle=\"yes\">blaZ<\/jats:italic>\n                      expression, and time-kill assays. All BORSA isolates were cefoxitin-susceptible, \u03b2-lactamase-positive, and distributed across six clonal backgrounds, with ST25 and ST7 each represented by three isolates. WGS identified a shared GdpP N105D substitution in all isolates, together with lineage-associated variations in\n                      <jats:italic toggle=\"yes\">pbp1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">pbp4<\/jats:italic>\n                      . Following oxacillin exposure,\n                      <jats:italic toggle=\"yes\">blaZ<\/jats:italic>\n                      was significantly upregulated in all three ST25 isolates (all\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.001), accompanied by accelerated nitrocefin hydrolysis, whereas the remaining isolates showed weaker or more heterogeneous responses. While oxacillin monotherapy (1\u00d7 MIC) failed to prevent bacterial regrowth, oxacillin\/sulbactam combinations produced sustained synergistic killing. This effect was most consistently observed among the ST25 isolates, whereas the ST7 isolates showed greater phenotypic variation. These findings suggest that the BORSA phenotype in this cohort may involve a multifactorial resistance profile, including candidate\n                      <jats:italic toggle=\"yes\">gdpP<\/jats:italic>\n                      variation, inducible \u03b2-lactamase activity, and alterations in penicillin-binding proteins (PBPs). The cefoxitin susceptibility of these isolates presents a diagnostic challenge that may lead to therapeutic misclassification and subsequent inappropriate therapy. \u03b2-lactam\/\u03b2-lactamase inhibitor combinations demonstrated promising\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      activity and warrants further investigation for BORSA isolates exhibiting strong inducible \u03b2-lactamase activity.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Borderline oxacillin-resistant\n                        <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                        (BORSA) is difficult to detect because it lacks\n                        <jats:italic toggle=\"yes\">mecA<\/jats:italic>\n                        \/\n                        <jats:italic toggle=\"yes\">mecC<\/jats:italic>\n                        and remains susceptible to cefoxitin, increasing the risk of misclassification and inappropriate \u03b2-lactam therapy. This study suggests that BORSA resistance in this cohort is multifactorial, involving candidate\n                        <jats:italic toggle=\"yes\">gdpP<\/jats:italic>\n                        variation, lineage-associated variations in penicillin-binding proteins, and inducible \u03b2-lactamase activity. Importantly, the ST25 isolates in this cohort exhibited rapid\n                        <jats:italic toggle=\"yes\">blaZ<\/jats:italic>\n                        induction and stronger responses to oxacillin\/sulbactam than to oxacillin alone. These findings improve understanding of BORSA biology, highlight a significant diagnostic blind spot in routine susceptibility testing, and support further evaluation of \u03b2-lactam\/\u03b2-lactamase inhibitor combinations as a promising treatment strategy for BORSA isolates exhibiting strong inducible \u03b2-lactamase activity.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.01352-26","type":"journal-article","created":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T13:00:41Z","timestamp":1792674041000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Lineage-associated genomic features and phenotypic heterogeneity in clinical borderline oxacillin-resistant\n                    <i>Staphylococcus aureus<\/i>"],"prefix":"10.1128","author":[{"given":"Qiyu","family":"Bian","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013q1eq08","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Antibiotics, Huashan Hospital, Fudan University","place":["Shanghai, China"]},{"name":"Key Laboratory of Clinical Pharmacology of Antibiotics, National Health Commission","place":["Shanghai, China"]},{"name":"Joint Laboratory of Hospital & Enterprise for Pathogen Diagnosis of Drug-resistant Bacterial lnfections and lnnovative Drug R&D","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Xi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013q1eq08","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Antibiotics, Huashan Hospital, Fudan University","place":["Shanghai, China"]},{"name":"Key Laboratory of Clinical Pharmacology of Antibiotics, National Health Commission","place":["Shanghai, China"]},{"name":"Joint Laboratory of Hospital & Enterprise for Pathogen Diagnosis of Drug-resistant Bacterial lnfections and lnnovative Drug R&D","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shilong","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013q1eq08","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hantian","family":"Fang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00t33hh48","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital","place":["Shatin, 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