Unravelling potential molecular targets of quercetin antibacterial activity against Staphylococcus aureus-infected wound through gene network, in silico, and in vitro approaches

Introduction: Staphylococcus aureus is a pathogenic bacterium commonly present in chronic wounds and can contribute to clinical complications, particularly among diabetic patients. Quercetin is a natural flavonoid with outstanding antioxidant and antibacterial properties. This study aimed to elucidate the molecular mechanisms of quercetin in modulating S. aureus-infected wound healing, particularly by identifying key target genes, in silico molecular docking verification, and investigating its in vitro antibacterial properties. Methods: A bioinformatics investigation was conducted to identify interrelated genes, using a Venn diagram and protein–protein interaction (PPI) analysis. Hub genes were identified using the Maximal clique centrality (MCC) and Density of maximum neighbourhood component (DMNC) algorithms. Molecular docking assessed interactions between quercetin and key targets (TP۵۳ and CYP۳A۴), followed by in vitro validation of quercetin’s antibacterial activity against S. aureus. Results: Protein-protein interaction (PPI) and Gene Ontology (GO) analyses showed that quercetin regulates the genes involved in apoptosis (TP۵۳, MCL۱), oxidative stress (CYP۳A۴, CYP۲E۱), and the insulin-related pathway (INS, SLC۲A۲, HNF۱A). TP۵۳, INS, and CYP۳A۴ exhibited the highest DMNC and MCC scores. Quercetin bound to CYP۳A۴ (–۶.۷۴ kcal/mol) and TP۵۳ (–۵.۸۹ kcal/mol), and stabilized by multiple hydrogen and hydrophobic interactions. In vitro antibacterial assays confirmed that quercetin inhibited S. aureus growth in a dose-dependent manner with MIC and IC۵۰ values of ۶۲.۵ and ۱۱۱.۲۳ µg/mL, respectively. Conclusion: The integrated gene network and molecular interaction approach highlight quercetin’s potential as a bioactive compound for accelerating healing in infected and diabetic wounds.