Synthesis and antimicrobial evaluation of novel quaternary quinolone derivatives with low toxicity and anti-biofilm activity

Abstract

To overcome the increasing global drug resistance, the development of novel antimicrobial drugs is a top priority in the fight against multidrug resistant (MDR) and persistent bacteria. In this work, we report the synthesis of novel single quaternary quinolone antibacterial agents. The majority of the tested compounds exhibited significant antimicrobial efficacy against Gram-negative pathogens (E. coli and S. maltophilia). Notably, the selected compound (4e) was highly inhibitory with a MIC value of 0.25 μg/mL against E. coli. Additionally, compound 4e demonstrated excellent stability in complex biological fluids with low hemolytic activity (HC₅₀ > 1280 μg/mL) and a significantly lower propensity to induce bacterial resistance. Encouragingly, 4e showed not only rapid bactericidal activity and inhibition of bacterial biofilms, but also low toxicity to erythrocytes and RAW 264.7 cells compared to the clinical drug ciprofloxacin. Mechanism studies have found that compound 4e has a relatively weak destructive effect on the cell membrane of E. coli. However, it can effectively inhibit the activity of glutathione (GSH), promote the massive accumulation of intracellular reactive oxygen species (ROS), and then disrupt the antioxidant defense system of bacteria, achieving a bactericidal effect. In addition, compound 4e has a certain binding effect with bacterial DNA.

Keywords: Antibacterial; Bacterial biofilm; Low-toxicity; Quinolone; ROS.