Improving the antimicrobial efficacy against resistant <i>Staphylococcus aureus</i> by a combined use of conjugated oligoelectrolytes

Two membrane-intercalating conjugated oligoelectrolytes (COEs), namely COE-D8 and COE-S6, were combined to achieve enhanced antimicrobial efficacy. COE-D8 has a shorter molecular length than COE-S6 and is typical of effective antimicrobial COE molecules, presumably due to its prominent membrane disrupting function. In contrast, COE-D6 exhibits lower efficacy against bacteria and lower toxicity toward mammalian cells. Surprisingly, after supplementing 8 μM COE-S6, the minimum inhibitory concentration (MIC) of COE-D8 against methicillin-resistant Staphylococcus aureus (MRSA) was improved 8-fold, from 0.5 μM to 0.063 μM (0.050 μg mL−1). No increased toxicity toward mammalian cells was observed by the combination of COEs, as indicated by cytotoxicity measurements using the 3T3 cell line. Indeed, there is an extended ratio between the half maximal inhibitory concentration based on 3T3 cells to MIC against MRSA from 12 to greater than 256. Biophysical experiments using liposome models suggest that COE-S6 promotes the interactions between COE-D8 and lipid bilayers, which is in agreement with damages of cellular permeability and morphology, as observed by confocal microscopy and scanning electron microscopy. The application of a combined mixture of COEs further demonstrates their promising potential as a new class of antimicrobial agents with high efficacy and selectivity.本研究将两种膜嵌入型共轭寡电解质（conjugated oligoelectrolytes，COEs）——COE-D8与COE-S6复配，以获得增强的抗菌效能。COE-D8的分子长度短于COE-S6，作为典型的高效抗菌COE分子，其活性推测源于突出的膜破坏功能。与之相反，COE-D6对细菌的抑菌效力更低，且对哺乳动物细胞的毒性也更弱。令人意外的是，在添加8 μM COE-S6后，COE-D8对耐甲氧西林金黄色葡萄球菌（methicillin-resistant Staphylococcus aureus，MRSA）的最低抑菌浓度（minimum inhibitory concentration，MIC）从0.5 μM降至0.063 μM（0.050 μg mL−1），抗菌效能提升8倍。通过3T3细胞系开展的细胞毒性检测结果显示，COEs复配并未增加对哺乳动物细胞的毒性。事实上，基于3T3细胞的半数抑制浓度与抗MRSA的MIC之间的比值，从12拓展至大于256。采用脂质体模型进行的生物物理实验表明，COE-S6可促进COE-D8与脂质双分子层的相互作用，这与共聚焦显微镜及扫描电子显微镜观察到的细胞通透性与形态损伤结果一致。将COEs复配混合物应用于抗菌体系，进一步证明这类新型抗菌剂兼具高效性与选择性，具备良好的应用潜力。