Targeted isolation of FabG inhibitors from Koelreuteria bipinnata leaves: Mechanistic insights, synergistic antibacterial effects, and cytoprotection.

Koelreuteria species serve as valuable sources of bioactive phytochemicals. This study explored the potential of chemical constituents derived from Koelreuteria bipinnata leaves as multifunctional natural ingredients for cosmetic applications. Through bioassay-guided fractionation targeting β-ketoacyl-acyl carrier protein reductase (FabG), 12 compounds were isolated and identified. Notably, five galloylated flavonoid glycosides were discovered as previously unreported FabG inhibitors. Among them, quercetin-3-O-(2″-O-galloyl)-rhamnoside (QGR) displayed the most potent FabG inhibitory activity (IC50 = 44.16 μM), acting as a competitive and uncompetitive inhibitor with respect to the substrate and cofactor, respectively. Molecular docking revealed that QGR interacts with the Lys155, Leu58, and Gly12 residues of FabG via hydrogen bonds. Furthermore, QGR exhibited notable synergism with methylparaben against Staphylococcus aureus (fractional inhibitory concentration index, FICI = 0.375), thereby formulating a novel synergistic combination of a natural product and a paraben preservative. Additionally, QGR demonstrated robust antioxidant capacity, with an IC50 of 13.0 μM for ABTS radical scavenging, and significantly protected normal human immortalized keratinocytes (HaCaT) cells against H2O2-induced oxidative damage, increasing cell viability from 71.25% to 92.56%. These findings highlight that galloylated flavonoid glycosides from K. bipinnata leaves are promising natural candidates for developing safe and multifunctional cosmetic ingredients.