铁载体偶联抗生素连接体优化的研究进展

Research advances of linkers in the design of siderophore-antibiotic conjugates

摘要:

由于抗生素的滥用，细菌耐药性问题日益严峻。细菌耐药性特别是革兰氏阴性菌耐药性已经成为主要公共卫生威胁之一。将细菌分泌的铁载体分子与抗生素偶联，利用细菌的铁摄取系统将抗生素转运至细菌细胞内，从而增强药效或者扩大抗菌谱，称之为“特洛伊木马”策略。2019年，头孢地尔(cefiderocol)作为第一个铁载体-抗生素偶联药物被批准上市，引起研究人员对“特洛伊木马”分子抗生素策略的广泛关注。目前铁载体-抗生素偶联物的设计大都是考虑连接不同作用机制的抗生素或不同种类的铁载体，而缺乏对中间连接体的研究。本综述将归纳总结文献中不同连接体对偶联物抗菌活性的影响，可为新型抗菌药物研发、解决临床耐药问题提供参考。

Abstract:

Escalating resistance of pathogens, especially Gram-negative bacteria, to antibiotics has become a public health problem arousing worldwide concern because of the abuse of antibiotics. The “Trojan Horse” strategy emerges as a promising approach to the development of new antibacterial agents. This strategy improves the antibacterial activity or broadens the antibacterial spectrum of antibiotics by using the siderophore-mediated bacterial iron transport system. In 2019, cefiderocol as the first siderophore-antibiotic conjugate was approved for marketing, which has garnered wide attention of scientists in this field. Currently, researchers mainly focus on siderophores or utilizing antibiotics with different mechanisms and ignoring linkers in the design of agents based on the “Trojan Horse” strategy. This review will summarize the impact of different linkers of conjugates on antibacterial activity, which could provide reference for the development of new antibacterial drugs and combating bacterial resistance.