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<p>Bacterial biofilms, spatially and physiologically heterogeneous communities, protect pathogens from antibiotics and drive persistent infections, particularly those caused by the clinically challenging methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). Such biofilm-mediated protection poses a major obstacle to antibiotic therapy, rendering quinolone antibiotics markedly less effective owing to their limited penetration into the biofilm matrix and the intrinsic tolerance of sessile bacteria. Therefore, strategies capable of overcoming biofilm-associated resistance and restoring the therapeutic potential of legacy quinolone antibiotics are urgently needed. Herein, a multifunctional molecular platform, AFQ-BP, was rationally developed to serve as a dual antibiofilm and antibacterial agent. Nineteen novel derivatives were designed and synthesized, <b>21</b> and <b>22</b> exhibited strong antibacterial activity, comparable to that of frontline antibiotics such as ampicillin and ciprofloxacin. Notably, the lead candidate <b>22</b> (MIC = 2&#xa0;µg/mL against MRSA 21-5) suppressed biofilm formation by 69.6% and eradicated mature biofilms by 70.2%, demonstrating a 5-fold improvement over ciprofloxacin at 1×MIC and sustained activity even at the subinhibitory concentration of 1/4×MIC. It exhibited low cytotoxicity toward HEK293 cells (IC<sub>50</sub> &gt;100&#xa0;µg/mL), negligible hemolysis (1.05%), and acceptable lipophilicity (cLogP = 2.70), while being predicted as non-BBB permeant. Compound <b>12</b>, repurposed from the obsolete second-generation quinolone antibiotic pipemidic acid, reduced biofilm biomass by 67.0% at 1/4×MIC. Preliminary mechanistic studies suggest a multifaceted antibiofilm mechanism involving ROS amplification, EPS disintegration, and membrane damage.</p>

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A multifunctional molecular platform for restoration quinolone antibiotics: synthesis, antimicrobial, anti-biofilm and preliminary mechanistic studies

  • 期刊论文

  • 发表日期：

    2026年7月26日

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  • Xingyu Chen,
  • Jinxia Yang,
  • Chenxiao Wang,
  • Caimei Yao,
  • Hongsong Wang,
  • Yujiao He,
  • Xiaorong Yang,
  • Xin He,
  • Qian Yao,
  • Lan Lu,
  • Peng Sun,
  • Xiaoqiang Guo

摘要

Bacterial biofilms, spatially and physiologically heterogeneous communities, protect pathogens from antibiotics and drive persistent infections, particularly those caused by the clinically challenging methicillin-resistant Staphylococcus aureus (MRSA). Such biofilm-mediated protection poses a major obstacle to antibiotic therapy, rendering quinolone antibiotics markedly less effective owing to their limited penetration into the biofilm matrix and the intrinsic tolerance of sessile bacteria. Therefore, strategies capable of overcoming biofilm-associated resistance and restoring the therapeutic potential of legacy quinolone antibiotics are urgently needed. Herein, a multifunctional molecular platform, AFQ-BP, was rationally developed to serve as a dual antibiofilm and antibacterial agent. Nineteen novel derivatives were designed and synthesized, 21 and 22 exhibited strong antibacterial activity, comparable to that of frontline antibiotics such as ampicillin and ciprofloxacin. Notably, the lead candidate 22 (MIC = 2 µg/mL against MRSA 21-5) suppressed biofilm formation by 69.6% and eradicated mature biofilms by 70.2%, demonstrating a 5-fold improvement over ciprofloxacin at 1×MIC and sustained activity even at the subinhibitory concentration of 1/4×MIC. It exhibited low cytotoxicity toward HEK293 cells (IC50 >100 µg/mL), negligible hemolysis (1.05%), and acceptable lipophilicity (cLogP = 2.70), while being predicted as non-BBB permeant. Compound 12, repurposed from the obsolete second-generation quinolone antibiotic pipemidic acid, reduced biofilm biomass by 67.0% at 1/4×MIC. Preliminary mechanistic studies suggest a multifaceted antibiofilm mechanism involving ROS amplification, EPS disintegration, and membrane damage.