{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:13:05Z","timestamp":1788221585441,"version":"build-2803163510"},"reference-count":39,"publisher":"American Chemical Society (ACS)","issue":"33","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004704","name":"National Research Council of Thailand","doi-asserted-by":"publisher","award":["0401\/ 13547"],"award-info":[{"award-number":["0401\/ 13547"]}],"id":[{"id":"10.13039\/501100004704","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006749","name":"Burapha University","doi-asserted-by":"publisher","award":["FullTime 2569\/06"],"award-info":[{"award-number":["FullTime 2569\/06"]}],"id":[{"id":"10.13039\/501100006749","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Faculty of Allied Health Sciences, Burapha University","doi-asserted-by":"publisher","award":["AHS06\/2567"],"award-info":[{"award-number":["AHS06\/2567"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Although S. epidermidis is a skin commensal bacterium, it is thought to be a causative pathogen of skin infections. Prolonged and extensive use of antibiotics for skin infections, including ampicillin (AMP), has contributed to the increasing emergence of antibiotic-resistant bacteria and the shaping of skin commensal S. epidermidis into opportunistic pathogens. This highlights the urgent necessity for alternative therapeutic strategies to enhance antimicrobial efficiency and minimize toxic effects on host cells. The present study investigated the potential of berberine (BBR), with specific attention to AMP resistance and BBR as an antibiotic adjunct to conventional antibiotics against S. epidermidis. Minimum inhibitory concentration (MIC) was used to determine the antibacterial susceptibility profiles. BBR reduced the MIC of AMP against AMP-resistant S. epidermidis from 16 to 64 \u03bcg\/mL to 2\u201316 \u03bcg\/mL, and the fractional inhibitory concentration index (FICI) values of 0.3\u20130.5 confirmed the synergistic interactions of BBR and AMP in combination. A time-kill analysis of the BBR+AMP combination suggested bacteriostatic activity and synergistic interaction. An antibacterial resistance induction study of BBR and AMP, either alone or in combination, demonstrated no substantial change in MIC in BBR alone and BBR+AMP over 15 consecutive passages. S. epidermidis isolates harboring resistant genes determined by the multiplex polymerase chain reaction (PCR) revealed multiple resistance genes (mecA, blaZ, aacA, and tetK). The effects of the BBR+AMP combination were visualized using scanning electron microscopy (SEM) and exhibited abnormal septation and cell surface damage. Propidium iodide (PI) and SYTO-9 demonstrated that the BBR+AMP combination disrupted membrane integrity. The cytotoxicity effect of the combination of BBR+AMP on human keratinocyte skin cells (HaCaT) was determined by the MTT assay, which demonstrated no significant toxicity, and a therapeutic index (TI) analysis suggested an acceptable safety margin. These findings support combinations of BBR and AMP as alternative therapeutics for the treatment of skin infections caused by AMP-resistant S. epidermidis.<\/jats:p>","DOI":"10.1021\/acsomega.6c00665","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T16:01:53Z","timestamp":1786377713000},"page":"49045-49053","source":"Crossref","is-referenced-by-count":0,"title":["Berberine Synergistically\nEnhances the Antibacterial\nActivity of Ampicillin against Ampicillin-Resistant\n                    <i>Staphylococcus epidermidis<\/i>"],"prefix":"10.1021","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6771-5362","authenticated-orcid":true,"given":"Htun Htun","family":"Win","sequence":"first","affiliation":[{"name":"Burapha University , , ,","place":["Chon Buri, Thailand, 20131"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Supphachai","family":"Onnom","sequence":"additional","affiliation":[{"name":"Burapha University , , ,","place":["Chon Buri, Thailand, 20131"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nipatchaya","family":"Sareephandon","sequence":"additional","affiliation":[{"name":"Burapha University , , ,","place":["Chon Buri, Thailand, 20131"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Supa","family":"Plangklang","sequence":"additional","affiliation":[{"name":"Burapha University , , ,","place":["Chon Buri, Thailand, 20131"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kittipot","family":"Sirichaiwetchakoon","sequence":"additional","affiliation":[{"name":"Burapha University , , ,","place":["Chon Buri, Thailand, 20131"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surachat","family":"Buddhisa","sequence":"additional","affiliation":[{"name":"Burapha University , , ,","place":["Chon Buri, Thailand, 20131"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nattaphol","family":"Prakobkaew","sequence":"additional","affiliation":[{"name":"Burapha University , , ,","place":["Chon Buri, Thailand, 20131"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjawan","family":"Dunkhunthod","sequence":"additional","affiliation":[{"name":"Phetchaburi Rajabhat University , , ,","place":["Phetchaburi, Thailand, 76000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peerapat","family":"Krittanan","sequence":"additional","affiliation":[{"name":"Burapha University , , ,","place":["Chon Buri, Thailand, 20131"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0387-8666","authenticated-orcid":true,"given":"Yothin","family":"Teethaisong","sequence":"additional","affiliation":[{"name":"Burapha University , , ,","place":["Chon Buri, Thailand, 20131"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"2026083119141296100_cit1","doi-asserted-by":"publisher","first-page":"3443","DOI":"10.2147\/CCID.S571984","article-title":"Skin Microbiome\nin Health and Disease: Mechanisms and Emerging Therapeutic Strategies","volume":"Volume 18","author":"Li","year":"2025","journal-title":"Clin., Cosmet. Invest. Dermatol."},{"issue":"5","key":"2026083119141296100_cit2","doi-asserted-by":"publisher","first-page":"1126","DOI":"10.3390\/LIFE13051126","article-title":"Difficult-to-Treat\nPathogens: A Review on the Management of Multidrug-Resistant Staphylococcus epidermidis","volume":"13","author":"Siciliano","year":"2023","journal-title":"Life"},{"issue":"6","key":"2026083119141296100_cit3","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1007\/s40257-020-00556-6","article-title":"Antibiotic Resistance in Acne: Mechanisms,\nComplications and Management","volume":"21","author":"Aslan Kayiran","year":"2020","journal-title":"Am. J. Clinical\nDermatol."},{"issue":"6","key":"2026083119141296100_cit4","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1016\/j.jaad.2021.11.066","article-title":"Part I\nAntimicrobial\nresistance: Bacterial pathogens of dermatologic significance and implications\nof rising resistance","volume":"86","author":"George","year":"2022","journal-title":"J. Am. Academy Dermatol."},{"issue":"1","key":"2026083119141296100_cit5","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1002\/bies.201200112","article-title":"Coagulase-negative\nstaphylococci as reservoirs of genes facilitating MRSA infection","volume":"35","author":"Otto","year":"2013","journal-title":"BioEssays"},{"issue":"5","key":"2026083119141296100_cit6","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1093\/gbe\/evv066","article-title":"Ecological Overlap and Horizontal Gene Transfer\nin Staphylococcus aureus and Staphylococcus epidermidis","volume":"7","author":"Me\u0301ric","year":"2015","journal-title":"Genome Biol. 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Sci. Asia"},{"issue":"9","key":"2026083119141296100_cit10","doi-asserted-by":"publisher","first-page":"1935","DOI":"10.1007\/s00705-020-04706-3","article-title":"Antiviral\nactivity of berberine","volume":"165","author":"Warowicka","year":"2020","journal-title":"Arch. Virol."},{"issue":"5","key":"2026083119141296100_cit11","first-page":"5217","article-title":"Antibacterial activity and mechanism of berberine against Streptococcus agalactiae","volume":"8","author":"Peng","year":"2015","journal-title":"Int. J.\nClin. Exp. Pathol."},{"key":"2026083119141296100_cit13","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.917414","article-title":"A New Perspective on the Antimicrobial\nMechanism of Berberine Hydrochloride Against Staphylococcus aureus Revealed by Untargeted Metabolomic Studies","volume":"13","author":"Wu","year":"2022","journal-title":"Front. Microbiol."},{"issue":"5","key":"2026083119141296100_cit14","doi-asserted-by":"publisher","first-page":"6583","DOI":"10.3390\/molecules19056583","article-title":"Berberine\nEnhances the Antibacterial\nActivity of Selected Antibiotics against Coagulase-Negative Staphylococcus\nStrains in Vitro","volume":"19","author":"Wojtyczka","year":"2014","journal-title":"Molecules"},{"issue":"10","key":"2026083119141296100_cit15","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1038\/ja.2016.15","article-title":"In vitro characterization and inhibition\nof the interaction between ciprofloxacin and berberine against multidrug-resistant\nKlebsiella pneumoniae","volume":"69","author":"Zhou","year":"2016","journal-title":"J. Antibiot."},{"issue":"7","key":"2026083119141296100_cit16","doi-asserted-by":"publisher","first-page":"947","DOI":"10.3390\/PH18070947","article-title":"Exploring\nthe Role of Berberine as a Molecular\nDisruptor in Antimicrobial Strategies","volume":"18","author":"Duda-Madej","year":"2025","journal-title":"Pharmaceuticals"},{"key":"2026083119141296100_cit17","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2021.114019","article-title":"Plant-derived nanotherapeutic systems to counter the\novergrowing threat of resistant microbes and biofilms","volume":"179","author":"Asghar","year":"2021","journal-title":"Adv. Drug Delivery Rev."},{"key":"2026083119141296100_cit18","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioflm.2023.100117","article-title":"Berberine\ndisrupts staphylococcal proton motive force to cause potent anti-staphylococcal\neffects in vitro","volume":"5","author":"Zhao","year":"2023","journal-title":"Biofilm"},{"issue":"2","key":"2026083119141296100_cit19","doi-asserted-by":"publisher","DOI":"10.1128\/SPECTRUM.03324-22","article-title":"Role of Berberine as\na Potential Efflux Pump Inhibitor against MdfA\nfrom Escherichia coli: In Vitro and\nIn Silico Studies","volume":"11","author":"Li","year":"2023","journal-title":"Microbiology Spectrum."},{"key":"2026083119141296100_cit20","doi-asserted-by":"publisher","first-page":"7313","DOI":"10.2147\/IDR.S431256","article-title":"Potentiation and Mechanism\nof Berberine as an Antibiotic Adjuvant Against Multidrug-Resistant\nBacteria","volume":"Volume 16","author":"Zhou","year":"2023","journal-title":"Infection Drug Resistance"},{"key":"2026083119141296100_cit21","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2025.1643409","article-title":"Berberine\nand its nanoformulations and extracts: potential\nstrategies and future perspectives against multi-drug resistant bacterial\ninfections","volume":"16","author":"Yang","year":"2025","journal-title":"Front. 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Agents Chemother."},{"key":"2026083119141296100_cit24","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.ijantimicag.2008.10.033","article-title":"Effect of berberine on Staphylococcus epidermidis biofilm formation","volume":"34","author":"Wang","year":"2009","journal-title":"Int.\nJ. Antimicrob. Agents"},{"issue":"2","key":"2026083119141296100_cit26","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1128\/AAC.03781-14","article-title":"Antisense\nGrowth Inhibition of Methicillin-Resistant Staphylococcus aureus by Locked Nucleic Acid Conjugated with Cell-Penetrating\nPeptide as a Novel FtsZ Inhibitor","volume":"59","author":"Meng","year":"2015","journal-title":"Antimicrob.\nAgents Chemother."},{"issue":"3","key":"2026083119141296100_cit27","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1128\/spectrum.01515-22","article-title":"Antimicrobial activity of a natural compound and analogs\nagainst multi-drug-resistant Gram-positive pathogens","volume":"12","author":"Shah","year":"2024","journal-title":"Microbiol. Spectrum"},{"key":"2026083119141296100_cit28","doi-asserted-by":"publisher","first-page":"621","DOI":"10.3389\/fmicb.2020.00621","article-title":"Berberine Damages the\nCell Surface of Methicillin-Resistant Staphylococcus aureus","volume":"11","author":"Zhang","year":"2020","journal-title":"Front. Microbiol."},{"issue":"3","key":"2026083119141296100_cit29","doi-asserted-by":"publisher","DOI":"10.1016\/j.arabjc.2024.105612","article-title":"Topical\napplication of berberine ameliorates imiquimod-induced\npsoriasis-like dermatitis in BALB\/c mice via suppressing JAK1\/STAT1\nsignaling pathway","volume":"17","author":"Chen","year":"2024","journal-title":"Arabian J. Chem."},{"key":"2026083119141296100_cit30","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/796306","article-title":"Effects\nof Berberine on Cell Cycle, DNA, Reactive Oxygen Species,\nand Apoptosis in L929 Murine Fibroblast Cells","volume":"2015","author":"Gu","year":"2015","journal-title":"Evidence-based Complementary and Alternative Medicine"},{"issue":"7","key":"2026083119141296100_cit31","doi-asserted-by":"publisher","first-page":"7459","DOI":"10.1021\/acs.jmedchem.4c03167","article-title":"Development of Membrane-Targeting Osthole Derivatives\nContaining\nPyridinium Quaternary Ammonium Moieties with Potent Anti-Methicillin-Resistant Staphylococcus aureus Properties","volume":"68","author":"Xu","year":"2025","journal-title":"J. Med. Chem."},{"issue":"1","key":"2026083119141296100_cit32","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-25714-z","article-title":"Synergistic\ncombination of two antimicrobial agents closing each other\u2019s\nmutant selection windows to prevent antimicrobial resistance","volume":"8","author":"Xu","year":"2018","journal-title":"Sci. Rep."},{"key":"2026083119141296100_cit33","volume-title":"Performance Standards\nfor Antimicrobial Disk Susceptibility Tests: Approved Standard","author":"Wikler","year":"2009"},{"issue":"10","key":"2026083119141296100_cit34","doi-asserted-by":"publisher","first-page":"4529","DOI":"10.1128\/AAC.00624-09","article-title":"In Vitro Activities\nof Panduratin A against Clinical Staphylococcus Strains","volume":"53","author":"Rukayadi","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026083119141296100_cit35","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.jgar.2017.10.019","article-title":"Boesenbergia rotunda (L.) Mansf. extract potentiates the antibacterial\nactivity of some \u03b2-lactams against \u03b2-lactam-resistant\nstaphylococci","volume":"12","author":"Teethaisong","year":"2018","journal-title":"J. Global Antimicrobial Resistance"},{"key":"2026083119141296100_cit36","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.533209","article-title":"In vitro Synergistic Activity of Antimicrobial\nCombinations Against blaKPC and blaNDM-Producing Enterobacterales With blaIMP or mcr Genes","volume":"11","author":"Zhou","year":"2020","journal-title":"Front. Microbiol."},{"key":"2026083119141296100_cit37","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.jgar.2019.01.012","article-title":"Nitro-Carba\ntest, a novel and simple chromogenic phenotypic method for rapid screening\nof carbapenemase-producing Enterobacteriaceae","volume":"18","author":"Teethaisong","year":"2019","journal-title":"J. Global Antimicrobial Resistance"},{"key":"2026083119141296100_cit38","doi-asserted-by":"publisher","DOI":"10.1155\/2023\/3453273","article-title":"Synergistic\nInteraction between Boesenbergia rotunda (L.) Mansf.\nEssential Oil and Cloxacillin on Methicillin-Resistant Staphylococcus aureus (MRSA) Inhibition","volume":"2023","author":"Apinundecha","year":"2023","journal-title":"Evid Based\nComplement Alternat Med."},{"key":"2026083119141296100_cit39","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-73766-1","article-title":"Antibacterial peptides from black soldier fly (Hermetia illucens) larvae: mode of action and characterization","volume":"14","author":"Pimchan","year":"2024","journal-title":"Sci. Rep."},{"key":"2026083119141296100_cit41","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2025.117975","article-title":"An optimized 2,2\u2032-dipicolylamine-rutaecarpine\nquaternary ammonium derivative: targeting bacterial membrane disruption\nfor enhanced anti-methicillin-resistant Staphylococcus aureus (MRSA) activity","volume":"297","author":"Xu","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"2026083119141296100_cit42","first-page":"273","volume-title":"Validation of In-vitro\nBioassay Methods: Application in Herbal Drug Research. Profiles of\nDrug Substances, Excipients and Related Methodology","author":"Indrayanto","year":"2021"}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.6c00665","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/33\/49045\/66477270\/acsomega.6c00665.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/33\/49045\/66477270\/acsomega.6c00665.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T23:14:18Z","timestamp":1788218058000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/11\/33\/49045\/5251464\/Berberine-Synergistically-Enhances-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,10]]},"references-count":39,"journal-issue":{"issue":"33","published-online":{"date-parts":[[2026,8,10]]},"published-print":{"date-parts":[[2026,8,25]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.6c00665","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,10]]}}}