Discovery of quaternary ammonium compounds with broad antibacterial activity and efficacy in S. aureus infection model.

Antimicrobial resistance (AMR) has become a significant global health concern, contributing heavily to the morbidity and mortality associated with both hospital-acquired (nosocomial) and community-acquired infections. In this context, we investigated the antibacterial potential of quinoline-based quaternary ammonium compounds (QACs) against Gram-positive bacteria, including multidrug-resistant (MDR) strains. Compound 20 was identified through a detail Structure-Activity-Relationship study and demonstrated strong antibacterial potential with an MIC of 0.125 μg/mL against S. aureus. This compound is effective against clinical MDR-MRSA and VRSA. Of note, 20 effectively inhibited bacterial growth in both planktonic and biofilm forms in a concentration-dependent manner. It's favorable toxicity profile (SI 72 w.r.t. CHO-K1 cells, HC50 of >100 μg/mL against human RBC) and prolonged post-antibiotic effect (PAE) compared to vancomycin highlights its potency as a safe therapeutic agent. Notably, the compound's in vitro efficacy was successfully translated in vivo, supporting its potential for development into a novel treatment for drug-resistant S. aureus infections, particularly for topical applications.