Development of cationic Pyridinium-Oxazolidinone derivatives as antibacterial agents

Drug-resistant bacteria and biofilm-associated infections remain major challenges in anti-infective therapy, contributing to high morbidity and mortality and emphasizing the need to develop novel antimicrobial agents with a low potential to induce resistance. Toward this, quaternization of compounds has become a viable molecular design approach for developing antibacterial agents. In this study, we report the design, synthesis, and antibacterial evaluation of a series of novel ring-C-modified quaternary ammonium oxazolidinone derivatives bearing various lipophilic substituents (alkyl- and aryl-moieties). The structure-activity relationship (SAR) exploration showed that the introduction of longer alkyl chains had a good effect on the antibacterial activity. Compound 4i with longest carbon chain exhibited potent antibacterial activity against E. faecalis with a MIC of 4 μg/mL. Furthermore, this pyridinium oxazolidinone not only exhibited a rapid bactericidal effect but also demonstrated a strong activity against E. faecalis biofilms, with no observable tendency for bacteria to develop resistance to 4i after 20 consecutive passages. Mechanistic studies revealed that 4i disrupted glutathione (GSH)/reactive oxygen species (ROS) homeostasis, thereby inducing lethal oxidative stress, leading to ROS accumulation and bacterial death. Compound 4i also showed low toxicity toward mammalian cells. Overall, our results suggest that incorporating quaternary ammonium salts into oxazolidinones will provide promising strategy for designing novel oxazolidinone derivatives with potent antimicrobial activity and low toxicity against mammalian cells.