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The use of antibiotic combinations, including antibiotics and antibiotic adjuvants, has proven effective in treating drug-resistant bacterial infections. This study evaluated the antibacterial effects of Ginsenoside Rh2 (G-Rh2) combined with\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      -lactam antibiotics against MRSA and investigated the underlying mechanisms. Checkerboard assays revealed that G-Rh2 and\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      -lactam antibiotics (cefoxitin, cefazolin, ampicillin, and meropenem) exhibit a synergistic antibacterial effect on MRSA. Bacterial growth curves showed that the combination of 12.5 \u03bcg\/mL G-Rh2 and sub-MIC\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      -lactam antibiotics effectively inhibited bacterial growth within 24 h. Morphological observation and measurement of intracellular component leakage indicated that the combination of G-Rh2 and cefoxitin (CFX) synergistically compromised the integrity of MRSA cell membranes. G-Rh2 alone had an anti-biofilm effect, and when combined with CFX, it exhibited a synergistic effect. The combination could significantly inhibit the formation of biofilms and eradicate mature biofilms. To elucidate the molecular basis of the synergistic antibacterial effect, transcriptomic analysis was performed. The data demonstrated that the synergy correlates with the downregulation of\n                      <jats:italic toggle=\"yes\">vraR<\/jats:italic>\n                      and genes within the\n                      <jats:italic toggle=\"yes\">dlt<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">pst<\/jats:italic>\n                      operons. Collectively, our results demonstrate that the combination of G-Rh2 and\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      -lactam antibiotics represents a promising therapeutic strategy against MRSA infections.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Methicillin-resistant\n                        <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                        (MRSA) is a formidable pathogenic bacterium capable of causing severe infections. This multidrug-resistant organism exhibits resistance to\n                        <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                        -lactam antibiotics, including penicillins, cephalosporins, and carbapenems. This study reveals that the natural compound Ginsenoside Rh2 (G-Rh2) can restore the susceptibility of MRSA to these antibiotics. When used in combination, G-Rh2 and\n                        <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                        -lactam antibiotics exhibit synergistic antibacterial activity, leading to compromised cell membrane integrity and disruption of biofilms. Moreover, G-Rh2 significantly delays the development of antibiotic resistance. These findings provide a promising new strategy for using natural products to combat antibiotic-resistant infections, which may extend the lifespan of existing antibiotics and improve the treatment outcomes for patients.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.00547-26","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T13:02:01Z","timestamp":1790600521000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Synergistic activity of Ginsenoside Rh2 with\n                    <i>\u03b2<\/i>\n                    -lactam antibiotics and its mechanism of action against methicillin-resistant\n                    <i>Staphylococcus aureus<\/i>"],"prefix":"10.1128","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9433-7450","authenticated-orcid":true,"given":"Ruihuan","family":"Chen","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05kvm7n82","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacy, Changshu Hospital Affiliated to Soochow University (Changshu No.1 People\u2019s Hospital)","place":["Changshu, China"]},{"id":[{"id":"https:\/\/ror.org\/03tqb8s11","id-type":"ROR","asserted-by":"publisher"}],"name":"College of Medicine, Yangzhou University","place":["Yangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3042-9476","authenticated-orcid":false,"given":"Lingyuan","family":"Guo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05g6ben79","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biological and Food Engineering, Suzhou University of Technology","place":["Changshu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimai","family":"Deng","sequence":"additional","affiliation":[{"name":"Molecular and Microbial Laboratory, Changshu Institution of Laboratory Medicine","place":["Changshu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaoyao","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Molecular and Microbial Laboratory, Changshu Institution of Laboratory Medicine","place":["Changshu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijie","family":"Cheng","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05kvm7n82","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacy, Changshu Hospital Affiliated to Soochow University (Changshu No.1 People\u2019s Hospital)","place":["Changshu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeqiong","family":"Xu","sequence":"additional","affiliation":[{"name":"Molecular and Microbial Laboratory, Changshu Institution of Laboratory Medicine","place":["Changshu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-018-0147-4"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)02185-7"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(24)00158-0"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2025.06.021"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)01867-1"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060614-034516"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2011.09.028"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI68834"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.726"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.887251"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2016.06.009"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13020-024-00960-8"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2024.155904"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.03227-23"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2024.01.003"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10266-024-00951-z"},{"key":"e_1_3_4_18_2","unstructured":"Clinical and laboratory standards institute. 2023. 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