Synthesis and Bioactivities of New Membrane-Active Agents with Aromatic Linker: High Selectivity and Broad-Spectrum Antibacterial Activity
Synthesis and Bioactivities of New Membrane-Active Agents with Aromatic Linker: High Selectivity and Broad-Spectrum Antibacterial Activity
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具有芳香连接基的新型膜活性剂的合成和生物活性：高选择性和广谱抗菌活性
DOI：
10.1021/acsinfecdis.9b00078
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发表时间：
2019-09-01
影响因子：
5.3
通讯作者：
Zhang, En
中科院分区：
文献类型：
--
作者：
Chu, Wenchao;Yang, Yi;Zhang, En
世界范围内出现的微生物对抗生素的耐药性构成了一个重要的、日益严重的公共健康威胁，迫切需要新的抗生素。本论文设计并合成了一系列芳香族原子核连接的对称型膜活化剂。部分菌株对临床分离的耐甲氧西林金黄色葡萄球菌(MRSA)、产碳青霉烯酶产气肠杆菌、德里产金属β-内酰胺酶-1肠杆菌科细菌(NDM-1)以及金黄色葡萄球菌、粪肠球菌、大肠埃希菌和嗜麦芽窄食单胞菌等敏感菌表现出较高的抗菌活性。先导化合物2n对金黄色葡萄球菌具有良好的选择性(最低抑菌浓度[MIC]0.25mU/mL)，对哺乳动物红细胞(溶血浓度[HC50]1211mU/mL)具有良好的选择性，具有在复杂哺乳动物体液中的稳定性，对病原体的快速杀灭，对已建立的生物被膜的清除能力，以及对细菌耐药性的诱导。在小鼠MRSA感染模型中，化合物2n在杀灭细菌和抑制炎症方面表现出与万古霉素相似的疗效，显示了其治疗潜力。
The worldwide emergence of microbial resistance to antibiotics constitutes an important and growing public health threat, and novel antibiotics are urgently needed. In this report, a series of symmetrical membrane-active agents linked by an aromatic nucleus were designed and synthesized. Some showed high antibacterial activity against clinical drug-resistant bacterial isolates including methicillin-resistant Staphylococcus aureus (MRSA), carbapenemase-producing Enterobacter aerogenes, and delhi metallo-beta-lactamase-1-producing Enterobacteriaceae (NDM-1), as well as drug-sensitive bacteria including Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Stenotrophomonas maltophilia. Lead compound 2n, with good selectivity for S. aureus (minimum inhibitory concentration [MIC] 0.25 mu g/mL) versus mammalian erythrocytes (hemolytic concentration [HC50] 1211 mu g/mL), had notable properties, including stability in complex mammalian fluids, rapid killing of pathogens, ability to eradicate established biofilms, and little induction of bacterial drug-resistance. In a mouse MRSA infection model, compound 2n exhibited a similar level of efficacy to vancomycin in killing bacteria and suppressing inflammation, demonstrating its therapeutic potential.