{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:38:18Z","timestamp":1790876298131,"version":"4.1.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32370184"],"award-info":[{"award-number":["32370184"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Science Foundation of Anhui Province, China","award":["2408085MC061"],"award-info":[{"award-number":["2408085MC061"]}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["WK9100000080"],"award-info":[{"award-number":["WK9100000080"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"name":"USTC Research Funds of the Double First-Class Initiative","award":["YD9100002063"],"award-info":[{"award-number":["YD9100002063"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The emergence of vancomycin-intermediate Staphylococcus aureus (VISA) has significantly challenged the treatment of S. aureus infection. Toxin\u2013antitoxin (TA) systems have been reported to mediate bacterial stress adaptation and virulence, but their role in vancomycin resistance remains elusive. This study investigated the vancomycin resistance mechanism regulated by the TA system SavRS in VISA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>savRS mutants in Mu50 and XN108 were generated via homologous recombination. To investigate the regulatory mechanism of vancomycin resistance mediated by savRS in VISA, phenotypic analyses including MICs, growth kinetics and cell wall thickness measurements were performed. Expression of cell wall synthesis-related genes was analysed using quantitative RT\u2013PCR (RT\u2013qPCR) and promoter-lacZ reporter assay. Electrophoretic mobility shift assay (EMSA) was performed to assess the binding of SavRS to the promoters of the cell wall synthesis-related genes. Pull-down assay identified an upstream regulatory element of savRS associated with vancomycin resistance. Quantitative assessment of bacterial burden in murine organ systems following vancomycin administration revealed the critical regulatory role of savRS in mediating vancomycin resistance in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Compared with the WT, the savRS mutant exhibited enhanced vancomycin sensitivity, accelerated growth and reduced cell wall thickness. Correspondingly, RT\u2013qPCR revealed marked down-regulation of the cell wall synthesis-related genes (glyS, dltA, scdA, pbp2, ddl). EMSA and promoter-lacZ reporter assay confirmed direct binding of SavRS to a conserved promoter motif, MGHYYTCCTCA. Pull-down assay identified UspA as an upstream regulator of SavRS, demonstrating that UspA directly controls savRS transcription and modulates VISA resistance. Mouse infection experiments showed that savRS promotes VISA to vancomycin resistance in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>SavRS critically regulates vancomycin resistance in VISA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jac\/dkaf325","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T11:57:16Z","timestamp":1758283036000},"page":"2978-2988","source":"Crossref","is-referenced-by-count":2,"title":["The toxin\u2013antitoxin system SavRS contributes to vancomycin resistance in vancomycin-intermediate\n                    <i>Staphylococcus aureus<\/i>\n                    by mediating cell wall thickening"],"prefix":"10.1093","volume":"80","author":[{"given":"Weifeng","family":"Xu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China , Hefei 230027 ,","place":["China"]},{"name":"Department of Oncology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China , Hefei, Anhui 230027 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Yan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China , Hefei 230027 ,","place":["China"]},{"name":"Department of Oncology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China , Hefei, Anhui 230027 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9293-6233","authenticated-orcid":false,"given":"Yujie","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China , Hefei 230027 ,","place":["China"]},{"name":"Department of Oncology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China , Hefei, Anhui 230027 ,","place":["China"]},{"name":"Anhui Province Key Laboratory of Embryo Development and Reproduction Regulation, Anhui Province Key Laboratory of Environmental Hormone and Reproduction, School of Biological and Food Engineering, Fuyang Normal University , Fuyang 236037 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2896-3015","authenticated-orcid":false,"given":"Baolin","family":"Sun","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China , Hefei 230027 ,","place":["China"]},{"name":"Department of Oncology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China , Hefei, Anhui 230027 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,9,23]]},"reference":[{"key":"2025110817244115900_dkaf325-B1","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1056\/NEJM199808203390806","article-title":"Staphylococcus aureus 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