Identification and heterologous expression of the globomycin biosynthetic gene cluster

作     者：Daniel Oves-Costales Tetiana Gren Eva Baggesgaard Sterndorff Jesús Martín Francisco Javier Ortiz-Lopez Tue S.Jørgensen Xinglin Jiang Fernando Roman-Hurtado Fernando Reyes Olga Genilloud Tilmann Weber 

作者机构：Fundacion MEDINACentro de Excelencia en Investigaci´on de Medicamentos Innovadores en AndalucíaAvda del Conocimiento 3418016ArmillaGranadaSpain The Novo Nordisk Foundation Center for BiosustainabilityTechnical University of DenmarkKemitorvetbuilding 2202800 Kgs.LyngbyDenmark 

出 版 物：《Synthetic and Systems Biotechnology》 (合成和系统生物技术（英文）)

年 卷 期：2023年第8卷第2期

页      面：206-212页

核心收录：

学科分类：07[理学] 070303[理学-有机化学] 0703[理学-化学] 0836[工学-生物工程] 

基　　金：funded by grants of the Novo Nordisk Foundation Denmark(NNF16OC0021746 to O.G. T.W. NNF20CC0035580 to T.W.). 

主　　题：Globomycin Signal peptidase II Cyclic lipodepsipeptide Genome mining CRISPR-cBEST Heterologous expression 

摘      要：Globomycin is a cyclic lipodepsipeptide originally isolated from several Streptomyces species which displays strong and selective antibacterial activity against Gram-negative pathogens.Its mode of action is based on the competitive inhibition of the lipoprotein signal peptidase II(LspA),which is absent in eukaryotes and considered an attractive target for the development of new antibiotics.Despite its interesting biological properties,the gene cluster encoding its biosynthesis has not yet been identified.In this study we employed a genome-mining approach in the globomycin-producing Streptomyces sp.CA-278952 to identify a candidate gene cluster responsible for its biosynthesis.A null mutant was constructed using CRISPR base editing where production was abolished,strongly suggesting its involvement in the biosynthesis.The putative gene cluster was then cloned and heterologously expressed in Streptomyces albus J1074 and Streptomyces coelicolor M1146,therefore unambigu-ously linking globomycin and its biosynthetic gene cluster.Our work paves the way for the biosynthesis of new globomycin derivatives with improved pharmacological properties.