大环内酯类抗生素代谢工程的研究进展

Advances in metabolic engineering of macrolide antibiotics

摘要:

14?16元环的大环内酯类抗生素 (Macrolide antibiotics，MA) 是临床上重要的抗感染药物。随着细菌耐药性的不断增加，迫切需要研发出新型MA来应对耐药菌。通过MA与核糖体靶点的相互作用可以指导MA的定向优化，结合快速发展的代谢工程方法可以高效获得所需的MA衍生物。近30年来，代谢工程在改造MA的生物合成获得新衍生物以及在提高其产量方面显示出巨大优势，这些代谢工程的方法包括改造聚酮合酶 (Polyketide synthase，PKS) 结构域和PKS后修饰酶以及组合生物合成等。另外，文中还对16元环大环内酯类新药可利霉素的研制过程、抗菌活性以及利用代谢工程优化其产生菌进行了详细介绍。

Abstract:

14- to 16-membered macrolide antibiotics (MA) are clinically important anti-infective drugs. With the rapid emergence of bacterial resistance, there is an urgent need to develop novel MA to counter drug-resistant bacteria. The targeted optimization of MA can be guided by analyzing the interaction between the MA and its ribosomal targets, and the desired MA derivatives can be obtained efficiently when combining with the rapidly developed metabolic engineering approaches. In the past 30 years, metabolic engineering approaches have shown great advantages in engineering the biosynthesis of MA to create new derivatives and to improve their production. These metabolic engineering approaches include modification of the structural domains of the polyketide synthase (PKS) and post-PKS modification enzymes as well as combinatorial biosynthesis. In addition, the R&D (including the evaluation of its antimicrobial activities and the optimization through metabolic engineering) of carrimycin, a new 16-membered macrolide drug, are described in details in this review.