Genomics Research Center, Academia Sinica, Taipei, Taiwan.
Nat Chem Biol. 2011 May;7(5):304-9. doi: 10.1038/nchembio.556. Epub 2011 Apr 10.
In the search for new efficacious antibiotics, biosynthetic engineering offers attractive opportunities to introduce minor alterations to antibiotic structures that may overcome resistance. Dbv29, a flavin-containing oxidase, catalyzes the four-electron oxidation of a vancomycin-like glycopeptide to yield A40926. Structural and biochemical examination of Dbv29 now provides insights into residues that govern flavinylation and activity, protein conformation and reaction mechanism. In particular, the serendipitous discovery of a reaction intermediate in the crystal structure led us to identify an unexpected opportunity to intercept the normal enzyme mechanism at two different points to create new teicoplanin analogs. Using this method, we synthesized families of antibiotic analogs with amidated and aminated lipid chains, some of which showed marked potency and efficacy against multidrug resistant pathogens. This method offers a new strategy for the development of chemical diversity to combat antibacterial resistance.
在寻找新的有效抗生素的过程中，生物合成工程为引入对抗生素结构的微小改变提供了有吸引力的机会，这些改变可能克服耐药性。Dbv29 是一种含有黄素的氧化酶，它催化万古霉素样糖肽的四电子氧化，生成 A40926。Dbv29 的结构和生化研究现在为控制黄素化和活性、蛋白质构象和反应机制的残基提供了深入了解。特别是，在晶体结构中偶然发现的一个反应中间体，使我们能够识别出在两个不同点拦截正常酶机制的意外机会，从而创造新的替考拉宁类似物。使用这种方法，我们合成了具有酰胺化和氨化脂质链的抗生素类似物家族，其中一些对多药耐药病原体表现出显著的效力和疗效。这种方法为开发对抗细菌耐药性的化学多样性提供了一种新策略。
