以大肠杆菌作为异源宿主完成红霉素A及设计类似物的生物合成。

Complete biosynthesis of erythromycin A and designed analogs using E. coli as a heterologous host.

作者信息

Zhang Haoran, Wang Yong, Wu Jiequn, Skalina Karin, Pfeifer Blaine A

机构信息

Department of Chemical & Biological Engineering, Tufts University, Medford, MA 02155, USA.

出版信息

Chem Biol. 2010 Nov 24;17(11):1232-40. doi: 10.1016/j.chembiol.2010.09.013.

DOI:10.1016/j.chembiol.2010.09.013

PMID:21095573

Abstract

Erythromycin A is a potent antibiotic long-recognized as a therapeutic option for bacterial infections. The soil-dwelling bacterium Saccharopolyspora erythraea natively produces erythromycin A from a 55 kb gene cluster composed of three large polyketide synthase genes (each ~10 kb) and 17 additional genes responsible for deoxysugar biosynthesis, macrolide tailoring, and resistance. In this study, the erythromycin A gene cluster was systematically transferred from S. erythraea to E. coli for reconstituted biosynthesis, with titers reaching 10 mg/l. Polyketide biosynthesis was then modified to allow the production of two erythromycin analogs. Success establishes E. coli as a viable option for the heterologous production of erythromycin A and more broadly as a platform for the directed production of erythromycin analogs.

摘要

红霉素A是一种强效抗生素，长期以来一直被视为治疗细菌感染的一种选择。土壤中生存的细菌糖多孢红霉菌天然地从一个由三个大的聚酮合酶基因（每个约10 kb）和另外17个负责脱氧糖生物合成、大环内酯修饰及抗性的基因组成的55 kb基因簇中产生红霉素A。在本研究中，红霉素A基因簇被系统地从糖多孢红霉菌转移至大肠杆菌以进行重组生物合成，产量达到10 mg/l。然后对聚酮生物合成进行修饰以允许生产两种红霉素类似物。这一成功确立了大肠杆菌作为红霉素A异源生产的可行选择，更广泛地作为定向生产红霉素类似物的一个平台。