Effective ciprofloxacin cationic antibacterial agent against persister bacteria with low hemolytic toxicity

With the widespread use of Antibiotics, Bacterial resistance has developed rapidly. To make matters worse, infections caused by persistent bacteria and biofilms often cannot be completely eliminated, which brings great difficulties to clinical medication. In this work, three series of Quinolone pyridinium quaternary ammonium small molecules were designed and synthesized. Most of the compounds showed good Antibacterial activity against Gram-positive bacteria (S. aureus and E. faecalis) and Gram-negative bacteria (E. coli and S. maltophilia). The activity of the para-pyridine quaternary ammonium salt was better than that of the meta-pyridine. 3f was the optimal compound with good stability in body fluids and was unlikely to induce Bacterial resistance. The hemolysis rate of erythrocytes at 1280 μg/mL for 3f was only 5.1%. Encouragingly, 3f rapidly killed bacteria within 4 h at 4 × MIC concentration and was effective in killing persistent bacteria in biofilms. The Antibacterial mechanism experiments showed that 3f could cause disorder of Bacterial membrane potential, increase Bacterial membrane permeability, dissolve and destroy the membrane. Incomplete Bacterial membranes lead to leakage of Bacterial genetic material, concomitant production of ROS, and Bacterial death due to these multiple effects.

Cationic antibacterial agent; Ciprofloxacin; Hemolytic toxicity; Persisters; Pyridine; Quinolone.