Abstract：
The development of bacterial resistance to the majority of clinically significant antimicrobials has made it more difficult to treat bacterial infections with conventional antibiotics. As part of ongoing research on antimicrobial peptide mimetics, a series of quaternary ammonium cationic compounds with various linkers were designed and synthesized, with some demonstrating high antibacterial activity against Gram-negative and Gram-positive bacteria. The structure-activity relationship study revealed that the spatial position of substituents had a significant impact on antibacterial activity and hemolytic toxicity. The best compound, 3e, has good antibacterial activity against Staphylococcus aureus [minimum inhibitory concentration (MIC = 1 μg/mL)] and the least hemolytic toxicity [hemolytic concentration (HC50 = 905 μg/mL)], is stable in mammalian body fluids, and rarely induces bacterial resistance. The mechanism study revealed that the membrane action mode may be its potential bactericidal mechanism, and it can effectively cause the accumulation of intracellular reactive oxygen species (ROS) for killing bacteria. Importantly, 3e can effectively reduce the load of methicillin-resistant Staphylococcus aureus (MRSA) in mouse skin and has a higher in vivo bactericidal efficiency than vancomycin. These findings highlight the significance of divergent linkers in quaternary ammonium cations as antimicrobial peptide mimics and the potential of these cations to treat bacterial infections.
摘要：
细菌对大多数临床上有意义的抗微生物剂的耐药性的发展使得用常规抗生素治疗细菌感染变得更加困难。作为抗菌肽模拟物正在进行的研究的一部分，设计并合成了一系列具有各种连接基的季铵阳离子化合物，其中一些表现出对革兰氏阴性和革兰氏阳性细菌的高抗菌活性。构效关系研究表明，取代基的空间位置对抗菌活性和溶血毒性有显著影响。最好的化合物，3e,对金黄色葡萄球菌具有良好的抑菌活性[最低抑菌浓度(MIC=1μg/mL)]和最小的溶血毒性[溶血浓度(HC50=905μg/mL)]，在哺乳动物体液中稳定，很少诱导细菌耐药性。机制研究表明，膜作用模式可能是其潜在的杀菌机制，能有效引起细胞内活性氧（ROS）的积累，从而杀死细菌。重要的是,3e能有效降低小鼠皮肤耐甲氧西林金黄色葡萄球菌(MRSA)的负荷,具有比万古霉素更高的体内杀菌效率。这些发现突出了季铵阳离子中不同接头作为抗微生物肽模拟物的重要性以及这些阳离子治疗细菌感染的潜力。
