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Effective ciprofloxacin cationic antibacterial agent against persister bacteria with low hemolytic toxicity
Chen Gao1, Shangshang Qin1, Meng Wang1
1School of Pharmaceutical Sciences, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China Zhengzhou University, Zhengzhou 450001, PR China.
Abstract:
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.
Insights
New quinolone pyridinium quaternary ammonium compounds combat antibiotic resistance. Compound 3f shows potent antibacterial activity against Gram-positive and Gram-negative bacteria, effectively eradicating biofilms with minimal toxicity.
Area of Science:
- Medicinal Chemistry
- Antimicrobial Research
- Drug Discovery
Background:
- Antibiotic resistance is a growing global health threat.
- Persistent bacterial infections and biofilms are challenging to treat clinically.
- Novel antimicrobial agents are urgently needed to overcome resistance.
Purpose of the Study:
- To design and synthesize novel quinolone pyridinium quaternary ammonium small molecules.
- To evaluate the antibacterial activity and biofilm eradication potential of synthesized compounds.
- To investigate the mechanism of action and safety profile of the lead compound.
Main Methods:
- Synthesis of three series of quinolone pyridinium quaternary ammonium compounds.
- In vitro antibacterial assays against Gram-positive and Gram-negative bacteria.
- Biofilm inhibition and eradication assays.
- Hemolysis assays to assess cytotoxicity.
- Mechanism of action studies including membrane potential and permeability.
Main Results:
- Most synthesized compounds exhibited significant antibacterial activity against tested bacteria.
- Para-pyridine quaternary ammonium salts demonstrated superior activity compared to meta-isomers.
- Compound 3f showed excellent stability, low resistance potential, and minimal hemolysis (5.1% at 1280 μg/mL).
- 3f rapidly killed planktonic bacteria and effectively eradicated bacteria within biofilms.
- Mechanism studies revealed membrane potential disruption, increased permeability, and cell lysis.
Conclusions:
- Quinolone pyridinium quaternary ammonium compounds represent a promising class of antimicrobials.
- Compound 3f is a potent candidate for treating bacterial infections, including those involving biofilms.
- 3f's mechanism involves multi-target disruption of bacterial membranes, leading to cell death.
