Benzo-γ-pyrone derivatives are widely utilized in both the food industry and pharmaceutical research.From a constructed Benzo-γ-pyrone Natural Compounds Database(BNCD),we screened 18 compounds with the core benzo-γ...Benzo-γ-pyrone derivatives are widely utilized in both the food industry and pharmaceutical research.From a constructed Benzo-γ-pyrone Natural Compounds Database(BNCD),we screened 18 compounds with the core benzo-γ-pyrone skeleton against Staphylococcus aureusα-hemolysin(Hla)and categorized them into five classes(A-E).We identified 10 effective inhibitors by hemolytic assay that could be pooled with the use of a doseresponse model to generate an IC50 curve.Dose-response analysis yielded IC50 values,which,together with molecular docking results for the Hla secretion regulators(AgrC,AgrA,SarR,SarA),revealed a key pharmaco-phore.The optimal structure is characterized by a benzo-γ-pyrone backbone featuring a C2-linked B-ring,an essential 5,7-dihydroxy motif on the A-ring,and a B-ring substituted with either a 4′-hydroxyl or a 3′,4′-catechol group.The minimum inhibitory concentrations(MICs)of morin,apigenin,(+/-)-naringenin,and liquiritigenin were all>2000μg/mL.Subsequent cytotoxicity assessments(CCK-8 assay)revealed no significant cytotoxicity(P>0.05)for morin and apigenin up to 2000μg/mL,for naringenin up to 500μg/mL,and for liquiritigenin up to 250μg/mL in bovine mammary epithelial cells.Furthermore,these compounds conferred concentration-dependent protection against S.aureus-induced damage in both in vitro Raw264.7 macrophage and in vivo Galleria mellonella larval infection models.In conclusion,our study identifies specific dietary benzo-γ-pyranones as promising non-antibiotic,anti-virulence agents targeting S.aureus Hla.These findings provide a rational basis for designing functional foods and developing novel anti-virulence therapeutics.展开更多
基金funded by the National Key R&D Program(2023YFD1800902)the Agricultural Science and Technology Innovation Program(ASTIP,No.IFR-06).
文摘Benzo-γ-pyrone derivatives are widely utilized in both the food industry and pharmaceutical research.From a constructed Benzo-γ-pyrone Natural Compounds Database(BNCD),we screened 18 compounds with the core benzo-γ-pyrone skeleton against Staphylococcus aureusα-hemolysin(Hla)and categorized them into five classes(A-E).We identified 10 effective inhibitors by hemolytic assay that could be pooled with the use of a doseresponse model to generate an IC50 curve.Dose-response analysis yielded IC50 values,which,together with molecular docking results for the Hla secretion regulators(AgrC,AgrA,SarR,SarA),revealed a key pharmaco-phore.The optimal structure is characterized by a benzo-γ-pyrone backbone featuring a C2-linked B-ring,an essential 5,7-dihydroxy motif on the A-ring,and a B-ring substituted with either a 4′-hydroxyl or a 3′,4′-catechol group.The minimum inhibitory concentrations(MICs)of morin,apigenin,(+/-)-naringenin,and liquiritigenin were all>2000μg/mL.Subsequent cytotoxicity assessments(CCK-8 assay)revealed no significant cytotoxicity(P>0.05)for morin and apigenin up to 2000μg/mL,for naringenin up to 500μg/mL,and for liquiritigenin up to 250μg/mL in bovine mammary epithelial cells.Furthermore,these compounds conferred concentration-dependent protection against S.aureus-induced damage in both in vitro Raw264.7 macrophage and in vivo Galleria mellonella larval infection models.In conclusion,our study identifies specific dietary benzo-γ-pyranones as promising non-antibiotic,anti-virulence agents targeting S.aureus Hla.These findings provide a rational basis for designing functional foods and developing novel anti-virulence therapeutics.
