Abstract：
The low permeability of the outer membrane of Gram-negative bacteria is a serious obstacle to the development of new antibiotics against them. Conjugation of antibiotic with siderophore based on the \"Trojan horse strategy\" is a promising strategy to overcome the outer membrane obstacle. In this study, series of antibacterial agents were designed and synthesized by conjugating the 3-hydroxypyridin-4(1H)-one based siderophores with cajaninstilbene acid (CSA) derivative 4 which shows good activity against Gram-positive bacteria by targeting their cell membranes but is ineffective against Gram-negative bacteria. Compared to the inactive parent compound 4, the conjugates 45c or 45d exhibits significant improvement in activity against Gram-negative bacteria, including Escherichia coli, Klebsiella pneumoniae and especially P. aeruginosa (minimum inhibitory concentrations, MICs = 7.8-31.25 μM). The antibacterial activity of the conjugates is attributed to the CSA derivative moiety, and the action mechanism is by disruption of bacterial cell membranes. Further studies on the uptake mechanisms showed that the bacterial siderophore-dependent iron transport system was involved in the uptake of the conjugates. In addition, the conjugates 45c and 45d showed a lower cytotoxic effects in vivo and in vitro and a positive therapeutic effect in the treatment of C. elegans infected by P. aeruginosa. Overall, our work describes a new class and a promising 3-hydroxypyridin-4(1H)-one-CSA derivative conjugates for further development as antibacterial agents against Gram-negative bacteria.
摘要：
革兰氏阴性菌外膜的低渗透性是开发针对它们的新抗生素的严重障碍。基于“特洛伊木马策略”将抗生素与铁载体缀合是克服外膜障碍的有前途的策略。在这项研究中,通过将基于3-羟基吡啶-4（1H）-酮的铁载体与卡扬替丁苯酸（CSA）衍生物4偶联来设计和合成一系列抗菌剂，该衍生物通过靶向其细胞膜而对革兰氏阳性细菌表现出良好的活性，但对革兰氏阴性细菌无效。与无活性的母体化合物4相比，缀合物45c或45d表现出针对革兰氏阴性细菌的活性的显着改善，包括大肠杆菌,肺炎克雷伯菌，尤其是铜绿假单胞菌（最低抑制浓度，MIC=7.8-31.25μM)。缀合物的抗菌活性归因于CSA衍生物部分，作用机制是通过破坏细菌细胞膜。对摄取机制的进一步研究表明，细菌铁载体依赖性铁转运系统参与了缀合物的摄取。此外,缀合物45c和45d在体内和体外显示出较低的细胞毒性效应，并且在治疗被铜绿假单胞菌感染的秀丽隐杆线虫方面具有积极的治疗作用。总的来说,我们的工作描述了一类新的和有前途的3-羟基吡啶-4（1H）-酮-CSA衍生物缀合物，用于进一步开发作为抗革兰氏阴性菌的抗菌剂。
