State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences , Peking University , Xue Yuan Road No.38 , Beijing 100191 , China.
Department of Chemistry , University of South Florida , 4202 E. Fowler Avenue , Tampa , Florida 33620 , United States.
J Med Chem. 2018 Apr 12;61(7):2865-2874. doi: 10.1021/acs.jmedchem.7b01704. Epub 2018 Mar 28.
Antibiotic resistance is one of the biggest threats to public health, and new antibacterial agents hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. Utilizing dimerization strategy, we rationally designed and efficiently synthesized a new series of small molecule dimeric lysine alkylamides as mimics of AMPs. Evaluation of these mimics against a panel of Gram-positive and Gram-negative bacteria including MDR strains was performed, and a broad-spectrum and potent compound 3d was identified. This compound displayed high specificity toward bacteria over mammalian cell. Time-kill kinetics and mechanistic studies suggest that compound 3d quickly eliminated bacteria in a bactericidal mode by disrupting bacterial cell membrane. In addition, lead compound 3d could inhibit biofilm formation and did not develop drug resistance in S. aureus and E. coli over 14 passages. These results suggested that dimeric lysine nonylamide has immense potential as a new type of novel small molecular agent to combat antibiotic resistance.
抗生素耐药性是对公众健康的最大威胁之一，因此需要新型抗菌剂来对抗由多药耐药（MDR）病原体引起的传染病。我们利用二聚化策略，合理设计并高效合成了一系列新型小分子二聚赖氨酸烷基酰胺作为 AMP 的模拟物。我们对包括 MDR 菌株在内的一系列革兰氏阳性和革兰氏阴性细菌进行了这些模拟物的评估，并鉴定出一种广谱且强效的化合物 3d。该化合物对细菌具有高度特异性，而对哺乳动物细胞则没有。时间杀伤动力学和机制研究表明，化合物 3d 通过破坏细菌细胞膜以杀菌模式快速消除细菌。此外，先导化合物 3d 可以抑制生物膜的形成，并且在金黄色葡萄球菌和大肠杆菌中经过 14 代传代也没有产生耐药性。这些结果表明，二聚赖氨酸壬酰胺具有作为新型小分子药物来对抗抗生素耐药性的巨大潜力。
