Metabolic Stress Induced by Quercetin Enhances Dormancy and Persistence in Staphylococcus aureus

<b>Background/Objectives</b>: The persistence of <i>Staphylococcus aureus</i> poses a significant challenge in clinical treatments because of its ability to withstand antibiotic therapy. This study assessed the role of quercetin in promoting bacterial dormancy and persistence through ATP depletion and revealed its potential impact on antibiotic tolerance. <b>Methods</b>: To assess the effects of quercetin on bacterial metabolism and persistence, <i>S. aureus</i> cultures were treated with quercetin, and intracellular ATP levels were then measured. The effect of quercetin on persister cell formation was assessed using antibiotic exposure assays, including pre-treatment and post-treatment strategies. <b>Results</b>: Quercetin treatment significantly depleted intracellular ATP levels in a dose-dependent manner, suggesting the presence of metabolic stress. This ATP depletion correlated with increased persister cell formation across multiple antibiotic treatments, indicating that quercetin-induced dormancy enhances bacterial persistence. Notably, quercetin pre-treatment further increased persister cell counts, while delayed quercetin administration increased persister cell survival, highlighting the influence of the timing of metabolic stress on persistence outcomes. <b>Conclusions</b>: Quercetin promotes bacterial persistence by inducing ATP depletion and metabolic dormancy. Although quercetin's bactericidal properties may initially impair bacterial growth, its potential to enhance persistence underscores the complexity of its effects. Further research is necessary to determine optimal strategies for harnessing the antimicrobial properties of quercetin while minimizing its persistence-promoting effects.