<br>开发针对耐甲氧西林金黄色葡萄球菌的膜靶向荧光 2-苯基-1H-菲[9,10-d]咪唑-抗菌肽模拟缀合物,Journal of Medicinal Chemistry

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开发针对耐甲氧西林金黄色葡萄球菌的膜靶向荧光 2-苯基-1H-菲[9,10-d]咪唑-抗菌肽模拟缀合物
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-03-16 , DOI: 10.1021/acs.jmedchem.4c00436
Ting Xu ₁ , Xiaoting Yan ₂ , Ayue Kang ₂ , Longhua Yang ₂ , Xinhui Li ₂ , Yue Tian ₂ , Ruige Yang _{1,

2} , Shangshang Qin ₂ , Yong Guo _{1,

2}

Affiliation

多重耐药细菌感染，特别是耐甲氧西林金黄色葡萄球菌（MRSA）引起的感染的升级，凸显了对新型抗菌药物的迫切需求。在这里，我们合成了一系列两亲性 2-苯基-1 H-菲并[9,10 -d ]咪唑-抗菌肽 (AMP) 模拟缀合物 ( III1 – 30 )。其中，化合物III13对G+细菌和临床MRSA分离株表现出优异的抗菌活性（MIC=0.5-2μg/mL）、膜选择性高、毒性低。此外，与传统临床抗生素相比， III13具有快速杀菌功效，且不易引起细菌耐药性。机理研究表明， III13靶向细菌膜上的磷脂酰甘油 (PG)，破坏膜完整性，导致细胞内 ROS 增加以及蛋白质和 DNA 泄漏，最终导致细菌细胞死亡。此外， III13具有良好的荧光特性，具有进一步动态监测抗菌过程的潜力。值得注意的是，与万古霉素相比， III13对 MRSA 表现出更好的体内疗效，表明其有潜力成为抗 MRSA 药物的有前途的候选药物。

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Development of Membrane-Targeting Fluorescent 2-Phenyl-1H-phenanthro[9,10-d]imidazole-Antimicrobial Peptide Mimic Conjugates against Methicillin-Resistant Staphylococcus aureus

The escalation of multidrug-resistant bacterial infections, especially infections caused by methicillin-resistant Staphylococcus aureus (MRSA), underscores the urgent need for novel antimicrobial drugs. Here, we synthesized a series of amphiphilic 2-phenyl-1H-phenanthro[9,10-d]imidazole-antimicrobial peptide (AMP) mimic conjugates (III1–30). Among them, compound III13 exhibited excellent antibacterial activity against G+ bacteria and clinical MRSA isolates (MIC = 0.5–2 μg/mL), high membrane selectivity, and low toxicity. Additionally, compared with traditional clinical antibiotics, III13 demonstrated rapid bactericidal efficacy and was less susceptible to causing bacterial resistance. Mechanistic studies revealed that III13 targets phosphatidylglycerol (PG) on bacterial membranes to disrupt membrane integrity, leading to an increase in intracellular ROS and leakage of proteins and DNA, ultimately causing bacterial cell death. Furthermore, III13 possessed good fluorescence properties with potential for further dynamic monitoring of the antimicrobial process. Notably, III13 showed better in vivo efficacy against MRSA compared to vancomycin, suggesting its potential as a promising candidate for anti-MRSA medication.

更新日期：2024-03-16

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