N-acetylcysteine promotes doxycycline resistance in the bacterial pathogen <i>Edwardsiella tarda</i>

Bacterial resistance poses a significant threat to both human and animal health. N-acetylcysteine (NAC), which is used as an anti-inflammatory, has been shown to have distinct and contrasting impacts on bacterial resistance. However, the precise mechanism underlying the relationship between NAC and bacterial resistance remains unclear and requires further investigation. In this study, we study the effect of NAC on bacterial resistance and the underlying mechanisms. Specifically, we examine the effects of NAC on <i>Edwardsiella tarda</i> ATCC15947, a pathogen that exhibits resistance to many antibiotics. We find that NAC can promote resistance of <i>E. tarda</i> to many antibiotics, such as doxycycline, resulting in an increase in the bacterial survival rate. Through proteomic analysis, we demonstrate that NAC activates the amino acid metabolism pathway in <i>E. tarda</i>, leading to elevated intracellular glutathione (GSH) levels and reduced reactive oxygen species (ROS). Additionally, NAC reduces antibiotic influx while enhancing efflux, thus maintaining low intracellular antibiotic concentrations. We also propose that NAC promotes protein aggregation, thus contributing to antibiotic resistance. Our study describes the mechanism underlying <i>E. tarda</i> resistance to doxycycline and cautions against the indiscriminate use of metabolite adjuvants.