Antibacterial Diamines Targeting Bacterial Membranes.
Antibacterial Diamines Targeting Bacterial Membranes.
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DOI：
10.1021/acs.jmedchem.5b01912
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发表时间：
2016-04-14
影响因子：
7.3
通讯作者：
Woster PM
中科院分区：
文献类型：
--
作者：
Wang B;Pachaiyappan B;Gruber JD;Schmidt MG;Zhang YM;Woster PM
抗生素耐药性对人类健康的威胁越来越大，缺乏新的抗生素更是雪上加霜。我们现在描述一系列取代二胺，它们对革兰氏阳性和革兰氏阴性细菌都能产生快速杀菌活性，包括耐甲氧西林金黄色葡萄球菌和固定期细菌。这些化合物减少了铜绿假单胞菌中生物膜的形成，促进了生物膜的扩散。最有效的类似物，3(1，13-bis{[(2，2-diphenyl)-1-ethyl]thioureido}-4，10-diazatridecane)，主要通过细胞质膜的去极化和细菌外膜的通透性起作用。透射电子显微镜证实，3迅速破坏了膜的完整性。棋盘法和时间-杀灭动力学实验表明，化合物3与卡那霉素也有协同作用。在人细胞毒性实验中，3个化合物对HEK293T人肾胚胎细胞和A549人腺癌细胞的毒性作用有限。此外，3对秀丽隐杆线虫的发育、存活和繁殖无不良影响。总体而言，与3相关的二胺代表了一类针对耐药病原体的新型广谱抗菌药。
Antibiotic resistance is a growing threat to human health exacerbated by a lack of new antibiotics. We now describe a series of substituted diamines that produce rapid bactericidal activity against both Gram-positive and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus and stationary-phase bacteria. These compounds reduce biofilm formation and promote biofilm dispersal in Pseudomonas aeruginosa. The most potent analogue, 3 (1,13-bis{[(2,2-diphenyl)-1-ethyl]thioureido}-4,10-diazatridecane), primarily acts by depolarization of the cytoplasmic membrane and permeabilization of the bacterial outer membrane. Transmission electron microscopy confirmed that 3 disrupts membrane integrity rapidly. Compound 3 is also synergistic with kanamycin, demonstrated by the checkerboard method and by time-kill kinetic experiments. In human cell toxicity assays, 3 showed limited adverse effects against the HEK293T human kidney embryonic cells and A549 human adenocarcinoma cells. In addition, 3 produced no adverse effects on Caenorhabditis elegans development, survival, and reproduction. Collectively, diamines related to 3 represent a new class of broad-spectrum antibacterials against drug-resistant pathogens.
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影响因子：
5.2
作者：
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通讯作者：
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影响因子：
7.3
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作者：
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