一种不易诱发耐药性的新型抗生素teixobactin的研究进展

Advances of teixobactin, a new antibiotic without detectable resistance

细菌耐药问题已经成为21世纪世界上最大的健康问题之一。发现新抗生素的速度越来越慢以及新耐药细菌的产生加速了新抗生素的需求。来源于难培养土壤微生物的缩肽类抗生素teixobactin具有独特新颖的抗菌机制,即和细菌细胞壁上肽聚糖前体脂质Ⅱ及壁磷壁酸前体脂质Ⅲ的保守序列结合,以致细菌细胞壁不能合成,可以杀死多种耐药性致病菌,包括耐甲氧西林金黄色葡萄球菌(methicillin-resistant Staphylococcus aureus, MRSA)和结核分枝杆菌(Mycobacterium tuberculosis)等。这种特殊的作用方式使病原体对其很难产生耐药性,因此,teixobactin被认为是"明星抗生素"。自teixobactin发现以来,它的生物活性、作用机制、构效关系等逐步被揭示,其化学全合成也得以实现,但是生物合成的研究相对滞后。本文总结了近几年来有关teixobactin的研究进展,讨论了其不易诱发耐药性的机制,并展望了其在生物合成方面的研究。

Bacterial resistance to existing drugs, a growing public concern worldwide, poses a threat to the health of humans. As the discovery of new antimicrobial drugs becomes extremely difficult and massive bacterial resistance emerges, it is urgent to search for new antibiotics. Teixobactin, a depsipeptide discovered in a screen of uncultured bacteria, inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid Ⅲ (precursor of cell wall teichoic acid) and kills a variety of drug-resistant pathogens, including clinically resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and Mycobaterium tuberculosis. Remarkably, since no teixobactin-resistant bacterial strains have been obtained due to its novel modes of action to kill pathogens, teixobactin has been considered to be a "star antibiotic". Since the discovery of teixobactin in 2015, its biological activity, modes of action, and structure-activity relationship (SAR) have been gradually revealed, and its total chemical synthesis has also been achieved, while the research on biosynthesis falls behind. This article summarizes the research progress of teixobactin in recent years, discusses the modes of actions that helps it kill pathogens without resistance development, and looks forward to the research on its biosynthesis.