2种氟喹诺酮类抗生素与群体感应抑制剂对E. coli的联合毒性效应
Joint Toxic Effects of Two Fluoroquinolones Antibiotics and Quorum Sensing Inhibitors on E. coli
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摘要: 抗生素滥用带来严重的细菌耐药性，威胁生态环境和人体健康。群体感应抑制剂（quorum sensing inhibitors，QSIs）作为一种理论上难以引发细菌耐药性的新型潜在抗生素替代品，被建议单独使用或与传统抗生素联合使用。因此，考察抗生素与QSIs联合作用效应及其作用机理对其在环境中可能产生的联合暴露风险评估具有重要的参考意义。以应用较广泛的2种氟喹诺酮类药物氧氟沙星（ofloxacin，OFL）、左氧氟沙星（levofloxacin，LEV）和1种新型抗菌剂群体感应抑制剂4-羟基-2，5-二甲基-3（2H）呋喃酮（4-hydroxy-2，5-dimethyl-3（2H）-furanone，HDMF）为研究对象，运用直接均分法和均匀设计射线法分别设计3个二元和1个三元混合物体系，每个体系包含5条具有不同组分浓度比的射线。应用时间毒性微板分析法测定3种药物及其混合物体系对大肠杆菌（Escherichia coli，E. coli）的毒性，应用拟合归零法分析混合物的毒性相互作用及相互作用强度，采用分子间对接技术来探讨可能存在的作用机理。结果表明，HDMF、OFL、LEV对E. coli均具有浓度、时间依赖毒性，以半数效应浓度负对数为毒性指标，3种药物在同一暴露时间毒性顺序：LEV>OFL>HDMF。3种药物的二元混合物体系相互作用类型有拮抗/协同作用，而三元混合物体系的作用类型为协同作用，且作用类型和强度受混合物组分、暴露时间和浓度影响。氟喹诺酮类药物混合物体系中，因药物竞争结合蛋白点位而呈现出拮抗作用。在氟喹诺酮类药物和QSIs混合体系中，QSIs会破坏细菌的生物膜，使氟喹诺酮类药物更容易接触细菌造成损伤，从而呈现协同作用。但随着暴露时间的延长，氟喹诺酮类药物会对DNA造成损伤进而减少QSIs作用蛋白的产生，呈现出拮抗作用。Abstract: The abuse of antibiotics has led to serious bacterial resistance, threatening the ecological environment and human health. Quorum sensing inhibitors (QSIs), as a new potential antibiotic alternative that is theoretically difficult to induce bacterial resistance, are recommended for use alone or in combination with traditional antibiotics. Therefore, the study on the combined effect of antibiotics and QSIs and its mechanism of action has important reference significance for the assessment of the combined exposure risks that may occur in the environment. Two widely used fluoroquinolone drugs, ofloxacin (OFL), levofloxacin (LEV), and one QSI, 4-hydroxy-2,5-dimethyl-3(2H)-furanone (HDMF) were selected as research objects in this study. Three binary and one ternary mixture systems of the three drugs were designed by direct equipartition and uniform design ray methods, respectively. Each system was arranged five rays with different component concentration ratios. The toxicity of the three drugs and their mixture systems against Escherichia coli (E. coli) was determined by the time-dependent toxicity microplate analysis method. Toxicity interactions and interaction strengths of the four mixture systems were analyzed by using a fit-to-zero method. Intermolecular docking technique was used to explore the possible mechanisms of action. The results showed that HDMF, OFL, LEV had toxic effects with concentration-/time- dependency on E. coli. By selecting the negative logarithm of the half effective concentration as the toxicity indicator, the toxicity order of the three drugs at the same exposure time was LEV>OFL>HDMF. The interaction type of the binary mixture system of the three drugs was antagonism/synergism, while the interaction type of the ternary mixture system was synergism, and the type and intensity of the interaction were affected by the components of the mixture, exposure time and components' concentration ratios. The fluoroquinolone mixture system exhibited antagonism because fluoroquinolones competed for binding protein sites. In the mixture system of fluoroquinolones and QSIs, QSIs could damage the biofilm of bacteria, making fluoroquinolones easier to contact bacteria and cause damage, thus presenting a synergistic effect. But fluoroquinolones would cause DNA damage and then reduce the production of QSIs acting proteins with the extension of exposure time, showing an antagonistic effect.
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