Abstract：
Global public health is facing a serious problem as a result of the rise in antibiotic resistance and the decline in the discovery of new antibiotics. In this study, two series of amphiphilic-cephalosporins were designed and synthesized, several of which showed good antibacterial activity against both Gram-positive and Gram-negative bacteria. Structure-activity relationships indicated that the length of the hydrophobic alkyl chain significantly affects the antibacterial activity against Gram-negative bacteria. The best compound 2d showed high activity against drug-susceptible Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA) with MICs of 0.5 and 2-4 μg/mL, respectively. Furthermore, 2d remained active in complex mammalian body fluids and had a longer post-antibiotic effect (PAE) than vancomycin. Mechanism studies indicated that compound 2d lacks membrane-damaging properties and can target penicillin-binding proteins to disrupt bacterial cell wall structure, inhibit the metabolic activity and induce the accumulation of reactive oxygen species (ROS) in bacteria. Compound 2d showed minimal drug resistance and was nontoxic to HUVEC and HBZY-1 cells with CC50 > 128 μg/mL. These findings suggest that 2d is a promising drug candidate for treating bacterial infections.
摘要：
由于抗生素耐药性的增加和新抗生素发现的减少，全球公共卫生面临着一个严重的问题。在这项研究中,设计并合成了两个系列的两亲性头孢菌素，其中一些对革兰氏阳性和革兰氏阴性细菌均显示出良好的抗菌活性。结构-活性关系表明，疏水性烷基链的长度显着影响对革兰氏阴性菌的抗菌活性。最佳化合物2d对药物敏感的金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌（MRSA）具有较高的活性，MIC分别为0.5和2-4μg/mL，分别。此外，2d在复杂的哺乳动物体液中保持活性并且具有比万古霉素更长的抗生素后效应(PAE)。机制研究表明，化合物2d缺乏膜损伤特性，可以靶向青霉素结合蛋白破坏细菌细胞壁结构，抑制细菌代谢活性并诱导活性氧（ROS）的积累。化合物2d显示最小的耐药性,对HUVEC和HBZY-1细胞无毒,CC50>128μg/mL。这些发现表明2d是治疗细菌感染的有希望的候选药物。
