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We integrated DIA quantitative proteomics, untargeted metabolomics, and protein\u2013ligand interaction analysis to elucidate this mechanism. Ninety differentially expressed proteins and 21 differential metabolites were identified. KEGG enrichment showed 19 overlapping pathways, 8 involved in \u03b2-h\/c biosynthesis. RT-qPCR confirmed significant downregulation of \u03b2-h\/c biosynthetic genes. Molecular docking revealed the strongest binding of baicalin to serine\/threonine kinase Stk1 (Vina score of \u221210.0), as confirmed by molecular dynamics simulation. The interaction was further validated by DARTS, DSF, and ITC. Site-directed mutagenesis identified Val93, Thr153, and Asp154 in Stk1\u2019s kinase domain as key binding residues. In vitro phosphorylation assays showed that baicalin inhibited Stk1-mediated CovR phosphorylation at T65, Y70, and T85, which underlies its inhibition of S. agalactiae \u03b2-h\/c activity. This study deepens understanding of baicalin\u2019s mechanism and provides a basis for its development as a bacterial virulence inhibitor.<\/jats:p>","DOI":"10.1021\/acs.jafc.5c14696","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T14:08:57Z","timestamp":1780668537000},"page":"18435-18454","source":"Crossref","is-referenced-by-count":0,"title":["Data-Independent Acquisition-Based Quantitative Proteomics,\nNontargeted Metabolomics, and Protein\u2013Ligand Interaction Reveal\nthe Mechanism of Baicalin Inhibiting \u03b2\n                    <i>-<\/i>\n                    hemolytic\/cytolytic\nActivities of\n                    <i>Streptococcus agalactiae<\/i>"],"prefix":"10.1021","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8047-5776","authenticated-orcid":true,"given":"Guihua","family":"Li","sequence":"first","affiliation":[{"name":"Hainan University , , , ,","place":["Haikou, Hainan, China, 570228"]},{"name":"Hainan University , , , ,","place":["Haikou, Hainan, China, 570228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaolong","family":"Liu","sequence":"additional","affiliation":[{"name":"Hainan University , , , ,","place":["Haikou, Hainan, China, 570228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zichen","family":"Zhao","sequence":"additional","affiliation":[{"name":"Hainan University , , , ,","place":["Haikou, Hainan, China, 570228"]},{"name":"Hainan University , , , ,","place":["Haikou, Hainan, China, 570228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jundi","family":"Shuli","sequence":"additional","affiliation":[{"name":"Hainan University , , , ,","place":["Haikou, Hainan, China, 570228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingli","family":"Xiang","sequence":"additional","affiliation":[{"name":"Hainan University , , , ,","place":["Haikou, Hainan, China, 570228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Hainan University , , , ,","place":["Haikou, Hainan, China, 570228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5805-7208","authenticated-orcid":true,"given":"Yun","family":"Sun","sequence":"additional","affiliation":[{"name":"Hainan University , , , ,","place":["Haikou, Hainan, China, 570228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihong","family":"Zhong","sequence":"additional","affiliation":[{"name":"Hainan University , , , ,","place":["Haikou, Hainan, China, 570228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shifeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Hainan University , , , ,","place":["Haikou, Hainan, China, 570228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Hainan University , , , ,","place":["Haikou, Hainan, China, 570228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5423-4471","authenticated-orcid":true,"given":"Weiliang","family":"Guo","sequence":"additional","affiliation":[{"name":"Hainan University , , , ,","place":["Haikou, Hainan, China, 570228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongcan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Hainan University , , , ,","place":["Haikou, Hainan, China, 570228"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"issue":"12","key":"2026073021175825500_cit1","doi-asserted-by":"publisher","first-page":"2002","DOI":"10.3201\/eid2312.170596","article-title":"Group B Streptococcus Infections Caused by Improper Sourcing and\nHandling of Fish for Raw Consumption, Singapore, 2015\u20132016","volume":"23","author":"Chau","year":"2017","journal-title":"Emerging Infect. Dis."},{"issue":"3","key":"2026073021175825500_cit2","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1016\/j.bjm.2017.02.004","article-title":"Molecular Epidemiology of Streptococcus Agalactiae Isolated from Mastitis in Brazilian Dairy Herds","volume":"48","author":"Carvalho-Castro","year":"2017","journal-title":"Braz. J. Microbiol."},{"issue":"6","key":"2026073021175825500_cit3","doi-asserted-by":"publisher","first-page":"1497","DOI":"10.1111\/jam.13447","article-title":"Molecular\nSerotyping, Virulence Gene Profiling and Pathogenicity of Streptococcus Agalactiae Isolated from Tilapia Farms in\nThailand by Multiplex PCR","volume":"122","author":"Kannika","year":"2017","journal-title":"J. Appl. Microbiol."},{"key":"2026073021175825500_cit4","doi-asserted-by":"publisher","first-page":"437","DOI":"10.3389\/fmicb.2018.00437","article-title":"Group B Streptococcal\nColonization, Molecular Characteristics,\nand Epidemiology","volume":"9","author":"Shabayek","year":"2018","journal-title":"Front Microbiol"},{"issue":"1","key":"2026073021175825500_cit5","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1186\/1471-2180-13-41","article-title":"Human Streptococcus\nAgalactiae Strains in Aquatic Mammals and Fish","volume":"13","author":"Delannoy","year":"2013","journal-title":"BMC Microbiol"},{"issue":"11","key":"2026073021175825500_cit6","doi-asserted-by":"publisher","first-page":"1974","DOI":"10.3201\/eid2211.160252","article-title":"Group B Streptococcus Sequence Type 283 Disease Linked to Consumption\nof Raw Fish, Singapore","volume":"22","author":"Rajendram","year":"2016","journal-title":"Emerging Infect. 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Antibiot (Tokyo)"},{"key":"2026073021175825500_cit13","doi-asserted-by":"publisher","first-page":"602","DOI":"10.3389\/fimmu.2018.00602","article-title":"Streptococcus Agalactiae Non-Pilus,\nCell Wall-Anchored\nProteins: Involvement in Colonization and Pathogenesis and Potential\nas Vaccine Candidates","volume":"9","author":"Pietrocola","year":"2018","journal-title":"Front. Immunol."},{"key":"2026073021175825500_cit14","doi-asserted-by":"publisher","DOI":"10.1016\/j.aquaculture.2019.734645","article-title":"Baicalin\nAttenuates Streptococcus Agalactiae Virulence and\nProtects Tilapia (Oreochromis Niloticus) from Group\nB Streptococcal Infection","volume":"516","author":"Wang","year":"2020","journal-title":"Aquaculture"},{"issue":"5","key":"2026073021175825500_cit15","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1111\/1574-6976.12071","article-title":"Group B Streptococcal Haemolysin and Pigment, a Tale of Twins","volume":"38","author":"Rosa-Fraile","year":"2014","journal-title":"FEMS\nMicrobiol Rev."},{"issue":"5","key":"2026073021175825500_cit16","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1172\/JCI17335","article-title":"Group B Streptococcal Beta-Hemolysin\/Cytolysin Activates Neutrophil Signaling Pathways in Brain\nEndothelium and Contributes to Development of Meningitis","volume":"112","author":"Doran","year":"2003","journal-title":"J. Clin. Invest."},{"issue":"4","key":"2026073021175825500_cit17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0060160","article-title":"The \u03b2-Hemolysin\nand Intracellular Survival of Streptococcus Agalactiae in Human Macrophages","volume":"8","author":"Sagar","year":"2013","journal-title":"PLoS One"},{"issue":"1","key":"2026073021175825500_cit18","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1128\/JCM.02177-15","article-title":"Molecular Characterization\nof Nonhemolytic and Nonpigmented Group B Streptococci Responsible for Human Invasive Infections","volume":"54","author":"Six","year":"2016","journal-title":"J. Clin Microbiol"},{"issue":"6","key":"2026073021175825500_cit19","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1084\/jem.20122753","article-title":"A Hemolytic Pigment of Group B Streptococcus Allows Bacterial Penetration of Human Placenta","volume":"210","author":"Whidbey","year":"2013","journal-title":"Journal of Experimental Medicine"},{"issue":"9","key":"2026073021175825500_cit20","doi-asserted-by":"publisher","first-page":"3818","DOI":"10.1128\/iai.64.9.3818-3826.1996","article-title":"Group B Streptococcal Beta-Hemolysin\nExpression Is Associated with Injury of Lung Epithelial Cells","volume":"64","author":"Nizet","year":"1996","journal-title":"Infect. Immun."},{"issue":"7","key":"2026073021175825500_cit21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002812","article-title":"The Pore-Forming Toxin \u03b2 Hemolysin\/Cytolysin\nTriggers P38 MAPK-Dependent IL-10 Production in Macrophages and Inhibits\nInnate Immunity","volume":"8","author":"Bebien","year":"2012","journal-title":"PLoS Pathog"},{"key":"2026073021175825500_cit22","doi-asserted-by":"publisher","first-page":"3123","DOI":"10.3389\/fmicb.2019.03123","article-title":"The Cyl Genes\nReveal the Biosynthetic\nand Evolutionary Origins of the Group B Streptococcus Hemolytic Lipid, Granadaene","volume":"10","author":"Armistead","year":"2020","journal-title":"Front. Microbiol."},{"issue":"1","key":"2026073021175825500_cit23","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1080\/13880209.2018.1492620","article-title":"A Comprehensive Review\non Phytochemistry, Pharmacology, and Flavonoid\nBiosynthesis of Scutellaria Baicalensis","volume":"56","author":"Wang","year":"2018","journal-title":"Pharm. Biol."},{"key":"2026073021175825500_cit24","doi-asserted-by":"publisher","first-page":"2861","DOI":"10.2147\/IDR.S406243","article-title":"Baicalein\nInhibits the Staphylococcus Aureus Biofilm and the\nLuxS\/AI-2 System in Vitro","volume":"16","author":"Mao","year":"2023","journal-title":"Infect. Drug Resist."},{"issue":"5","key":"2026073021175825500_cit25","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1046\/j.1365-2958.2003.03803.x","article-title":"Modulation\nof Pseudomonas Aeruginosa Gene Expression by Host\nMicroflora through Interspecies Communication","volume":"50","author":"Duan","year":"2003","journal-title":"Mol. Microbiol."},{"issue":"4","key":"2026073021175825500_cit26","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1099\/jmm.0.001179","article-title":"In Vitro Antivirulence Activity of\nBaicalin against Clostridioides Difficile","volume":"69","author":"Pellissery","year":"2020","journal-title":"J. Med. Microbiol."},{"issue":"4","key":"2026073021175825500_cit27","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1378\/chest.10-0166","article-title":"Pneumonia\nDue to Pseudomonas Aeruginosa","volume":"139","author":"Fujitani","year":"2011","journal-title":"Chest"},{"issue":"1","key":"2026073021175825500_cit28","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1186\/s12890-016-0339-5","article-title":"Cystic Fibrosis\nLung Environment and Pseudomonas Aeruginosa Infection","volume":"16","author":"Bhagirath","year":"2016","journal-title":"BMC Pulm. 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Infect."},{"issue":"2","key":"2026073021175825500_cit30","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1093\/infdis\/jis336","article-title":"Baicalin Protects Mice\nFrom Staphylococcus Aureus Pneumonia Via Inhibition\nof the Cytolytic Activity of \u03b1-Hemolysin","volume":"206","author":"Qiu","year":"2012","journal-title":"Journal of Infectious Diseases"},{"issue":"19","key":"2026073021175825500_cit31","doi-asserted-by":"publisher","first-page":"2773","DOI":"10.3390\/ani15192773","article-title":"Integrated Proteomics and Metabolomics\nProfiling Unravels Molecular Mechanisms Underlying Postmortem Meat\nQuality between Two Ages and Muscle Types in Sansui Duck","volume":"15","author":"Zhu","year":"2025","journal-title":"Animals"},{"issue":"11","key":"2026073021175825500_cit32","doi-asserted-by":"publisher","first-page":"1170","DOI":"10.1038\/s41374-022-00830-7","article-title":"High-Throughput Proteomics: A Methodological\nMini-Review","volume":"102","author":"Cui","year":"2022","journal-title":"Lab. 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Food Chem."},{"key":"2026073021175825500_cit34","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1186\/s13071-023-06030-6","article-title":"Transcriptomic and\nMetabolomic Analyses Reveal the Essential Nature\nof Rab1B in Toxoplasma Gondii","volume":"16","author":"He","year":"2023","journal-title":"Parasit Vectors"},{"key":"2026073021175825500_cit35","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2021.114798","article-title":"Drug Affinity Responsive\nTarget Stability (DARTS) Accelerated Small\nMolecules Target Discovery: Principles and Application","volume":"194","author":"Ren","year":"2021","journal-title":"Biochem. Pharmacol."},{"issue":"6141","key":"2026073021175825500_cit36","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1126\/science.1233606","article-title":"Monitoring Drug Target Engagement in Cells and Tissues\nUsing the Cellular Thermal Shift Assay","volume":"341","author":"Martinez Molina","year":"2013","journal-title":"Science"},{"issue":"1","key":"2026073021175825500_cit37","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1038\/nprot.2006.28","article-title":"Isothermal Titration\nCalorimetry to Determine Association\nConstants for High-Affinity Ligands","volume":"1","author":"Velazquez-Campoy","year":"2006","journal-title":"Nat. Protoc."},{"issue":"W1","key":"2026073021175825500_cit38","doi-asserted-by":"publisher","first-page":"W159","DOI":"10.1093\/nar\/gkac394","article-title":"CB-Dock2: Improved\nProtein\u2013Ligand Blind Docking by Integrating\nCavity Detection, Docking and Homologous Template Fitting","volume":"50","author":"Liu","year":"2022","journal-title":"Nucleic Acids Res."},{"issue":"42","key":"2026073021175825500_cit39","doi-asserted-by":"publisher","first-page":"28685","DOI":"10.1021\/jacs.4c04648","article-title":"Molecular Dynamics Unveils Multiple-Site\nBinding of Inhibitors with\nReduced Activity on the Surface of Dihydrofolate Reductase","volume":"146","author":"Araki","year":"2024","journal-title":"J. Am. Chem. Soc."},{"key":"2026073021175825500_cit40","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High\nPerformance\nMolecular Simulations through Multi-Level Parallelism from Laptops\nto Supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"issue":"11","key":"2026073021175825500_cit41","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.107851","article-title":"On the\nFunction of TRAP Substrate-Binding\nProteins: Conformational Variation of the Sialic Acid Binding Protein\nSiaP","volume":"300","author":"King-Hudson","year":"2024","journal-title":"J. Biol. Chem."},{"issue":"5","key":"2026073021175825500_cit42","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004088","article-title":"Dual-Site\nPhosphorylation of the Control of Virulence Regulator Impacts Group\na Streptococcal Global Gene Expression and Pathogenesis","volume":"10","author":"Horstmann","year":"2014","journal-title":"PLoS Pathog"},{"issue":"12","key":"2026073021175825500_cit43","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0243489","article-title":"The Plasticity\nof the Pyruvate Dehydrogenase Complex\nConfers a Labile Structure That Is Associated with Its Catalytic Activity","volume":"15","author":"Lee","year":"2020","journal-title":"PLoS One"},{"issue":"10","key":"2026073021175825500_cit44","doi-asserted-by":"publisher","first-page":"msad223","DOI":"10.1093\/molbev\/msad223","article-title":"Deciphering\nEvolutionary Trajectories of Lactate Dehydrogenases\nProvides New Insights into Allostery","volume":"40","author":"Robin","year":"2023","journal-title":"Mol. Biol.\nEvol."},{"key":"2026073021175825500_cit45","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.niox.2018.04.004","article-title":"Characterization of Human Triosephosphate\nIsomerase S-Nitrosylation","volume":"77","author":"Romero","year":"2018","journal-title":"Nitric Oxide"},{"key":"2026073021175825500_cit46","doi-asserted-by":"publisher","first-page":"18","DOI":"10.3389\/fmicb.2020.00018","article-title":"Environmental Triggers\nof lrgA Expression in Streptococcus Mutans","volume":"11","author":"Ishkov","year":"2020","journal-title":"Front. Microbiol."},{"issue":"44","key":"2026073021175825500_cit47","doi-asserted-by":"publisher","first-page":"27795","DOI":"10.1074\/jbc.271.44.27795","article-title":"Roles of the FabA\nand FabZ Beta-Hydroxyacyl-Acyl\nCarrier Protein Dehydratases in Escherichia Coli Fatty Acid Biosynthesis","volume":"271","author":"Heath","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2026073021175825500_cit48","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1007\/s13258-024-01541-7","article-title":"Transcriptome\nAnalysis of Tilapia Streptococcus Agalactiae in Response\nto Baicalin","volume":"47","author":"Huang","year":"2025","journal-title":"Genes Genomics"},{"issue":"16","key":"2026073021175825500_cit49","doi-asserted-by":"publisher","first-page":"5984","DOI":"10.1128\/JB.00768-05","article-title":"Transport of Multidrug Resistance\nSubstrates by the Streptococcus Agalactiae Hemolysin\nTransporter","volume":"188","author":"Gottschalk","year":"2006","journal-title":"J. Bacteriol."},{"issue":"2","key":"2026073021175825500_cit50","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0014658","article-title":"Two-Component System RgfA\/C Activates\nthe fbsB Gene Encoding Major Fibrinogen-Binding Protein in Highly\nVirulent CC17 Clone Group B Streptococcus","volume":"6","author":"Safadi","year":"2011","journal-title":"PLoS One"},{"issue":"1","key":"2026073021175825500_cit51","doi-asserted-by":"publisher","first-page":"9175","DOI":"10.1038\/s41467-024-53439-3","article-title":"Constitutive Activation of Two-Component Systems Reveals Regulatory\nNetwork Interactions in Streptococcus Agalactiae","volume":"15","author":"Claverie","year":"2024","journal-title":"Nat. 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