Wang Bo, Pachaiyappan Boobalan, Gruber Jordon D, Schmidt Michael G, Zhang Yong-Mei, Woster Patrick M
Department of Biochemistry and Molecular Biology, Medical University of South Carolina , Charleston, South Carolina 29425, United States.
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing, PR China.
J Med Chem. 2016 Apr 14;59(7):3140-51. doi: 10.1021/acs.jmedchem.5b01912. Epub 2016 Mar 28.
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.
抗生素耐药性对人类健康构成的威胁日益严重，而新抗生素的缺乏则加剧了这一威胁。我们现在描述了一系列取代二胺，它们对革兰氏阳性菌和革兰氏阴性菌均具有快速杀菌活性，包括耐甲氧西林金黄色葡萄球菌和处于稳定期的细菌。这些化合物可减少铜绿假单胞菌生物膜的形成并促进其生物膜的分散。最有效的类似物3（1,13-双{[(2,2-二苯基)-1-乙基]硫脲基}-4,10-二氮杂十三烷）主要通过使细胞质膜去极化和细菌外膜通透性增加而起作用。透射电子显微镜证实3能迅速破坏膜的完整性。棋盘法和时间-杀菌动力学实验表明化合物3与卡那霉素具有协同作用。在人类细胞毒性试验中，3对HEK293T人肾胚胎细胞和A549人腺癌细胞显示出有限的不良反应。此外，3对秀丽隐杆线虫的发育、存活和繁殖没有产生不良影响。总的来说，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剂。
