多重耐药菌的出现迫切需要发现具有新作用机制的抗生素。在本研究中，笔者将疏水的吖啶分子连接到核定位序列 (NLS) 的N末端合成了一种新型的抗菌药物Acr₃-NLS。为了进 一步提高该试剂的抗菌活性，笔者将两个单体Acr₃-NLS分子通过二硫键连接合成了二聚体(Acr₃-NLS)₂。结果显示，与NLS相比，Acr₃-NLS，特别是(Acr₃-NLS)₂，对革兰阴性菌和革兰阳性菌表现出显著的抗菌活性。随后，其作用机制的研究表明，Acr₃-NLS 和(Acr₃-NLS)₂ 可通过细胞膜破坏方式和DNA 结合方式杀死细菌。作用于细胞膜和细胞内DNA的双靶点抑杀机制可以降低细菌对Acr₃-NLS 和(Acr₃-NLS)₂ 产生耐药性的风险。总之， 本研究提供了一种新的策略，可用于设计具有双重作用机制的高效抗菌药物。

The emergence of multidrug-resistant bacteria creates an urgent need for alternative antibiotics with new mechanisms of action. In this study, we synthesized a novel type of antimicrobial agent, Acr₃-NLS, by conjugating hydrophobic acridines to the N-terminus of a nuclear localization sequence (NLS), a short cationic peptide. To further improve the antimicrobial activity of our agent, dimeric (Acr₃-NLS)₂ was simultaneously synthesized by joining two monomeric Acr₃-NLS together via a disulfide linker. Our results show that Acr₃-NLS and especially (Acr₃-NLS)₂ display significant antimicrobial activity against gram-negative and gram-positive bacteria compared to that of the NLS. Subsequently, the results derived from the study on the mechanism of action demonstrate that Acr₃-NLS and (Acr₃-NLS)₂ can kill bacteria by membrane disruption and DNA binding. The double targets–cell membrane and intracellular DNA–will reduce the risk of bacteria developing resistance to Acr₃-NLS and (Acr₃-NLS)₂. Overall, this study provides a novel strategy to design highly effective antimicrobial agents with a dual mode of action for infection treatment.