Synergistic Ionic Liquid-Antibiotic Combination as a Strategy against Methicillin-Resistant Staphylococcus aureus (MRSA).

The accelerating spread of antimicrobial resistance, particularly in methicillin-resistant Staphylococcus aureus (MRSA), demands innovative strategies to restore antibiotic efficacy. Repurposing small molecules as antibiotic adjuvants offers a rapid and translationally feasible solution. Here, we investigated chloroquine-derived ionic liquids (CQILs) as potentiators of conventional antibiotics against MRSA. Although the ILs displayed limited intrinsic antibacterial activity, the top candidate markedly reduced minimum inhibitory concentrations (MICs) in combination, demonstrating strong synergistic interactions with doxycycline and kanamycin (FICI = 0.29 and 0.41, respectively) and an additive interaction with chloramphenicol (FICI = 0.80). Time-kill analyses confirmed accelerated and sustained bactericidal activity relative to monotherapy. Mechanistic studies revealed enhanced intracellular reactive oxygen species accumulation and pronounced disruption of bacterial membrane integrity, corroborated by scanning electron microscopy, which showed severe morphological damage. Importantly, combination treatments achieved effective bacterial eradication at reduced antibiotic doses while maintaining low cytotoxicity toward mammalian cells, thereby improving the therapeutic window. These findings establish chloroquine-derived ionic liquids as promising antibiotic adjuvants that potentiate bactericidal activity through oxidative stress amplification and membrane destabilization, offering a practical strategy to combat multidrug-resistant bacterial infections.