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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Acr_3-NLS。为了进一步提高该试剂的抗菌活性,笔者将两个单体Acr_3-NLS分子通过二硫键连接合成了二聚体(Acr_3-NLS)_2。结果显示,与NLS相比,Acr_3-NLS,特别是(Acr_3-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,Acr_3-NLS和(Acr_3-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Acr_3-NLS和(Acr_3-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 multi-drug resistant bacteria urgently needs to find antibiotics with new mechanisms of action. In this study, a novel antibacterial agent named Acr_3-NLS was synthesized by attaching a hydrophobic acridine molecule to the N-terminus of the nuclear localization sequence (NLS). In order to further improve the antibacterial activity of this reagent, the authors synthesized Acr_3-NLS dimer (Acr_3-NLS) _2 by disulfide bond. The results showed that compared with NLS, Acr_3-NLS, especially (Acr_3-NLS) _2, showed significant antibacterial activity against Gram-negative and Gram-positive bacteria. Subsequently, its mechanism of action studies showed that Acr_3-NLS and (Acr_3-NLS) _2 can kill bacteria by means of cell membrane destruction and DNA binding. The dual target inhibition mechanism that acts on the cell membrane and intracellular DNA can reduce the risk of bacterial resistance to Acr_3-NLS and (Acr_3-NLS) _2. In conclusion, this study provides a new strategy for the design of highly effective antimicrobial agents with a dual mechanism of action.