title: Metabolic engineering of an industrial polyoxin producer for the targeted overproduction of designer nucleoside antibiotics.
abstract: Polyoxin and nikkomycin are naturally occurring peptidyl nucleoside antibiotics with potent antifungal bioactivity. Both exhibit similar structural features, having a nucleoside skeleton and one or two peptidyl moieties. Combining the refactoring of the polyoxin producer Streptomyces aureochromogenes with import of the hydroxypyridylhomothreonine pathway of nikkomycin allows the targeted production of three designer nucleoside antibiotics designated as nikkoxin E, F, and G. These structures were determined by NMR and/or high resolution mass spectrometry. Remarkably, the introduction of an extra copy of the nikS gene encoding an ATP-dependent ligase significantly enhanced the production of the designer antibiotics. Moreover, all three nikkoxins displayed improved bioactivity against several pathogenic fungi as compared with the naturally-occurring antibiotics. These data provide a feasible model for high efficiency generation of nucleoside antibiotics related to polyoxins and nikkomycins in a polyoxin cell factory via synthetic biology strategy.
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Jianzhao
authors.initials: J
authors.lastname: Qi
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wan
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: You-Sheng
authors.initials: YS
authors.lastname: Cai
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Yinghu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Shunying
authors.initials: S
authors.lastname: Li
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Wu
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Feng
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Guofu
authors.initials: G
authors.lastname: Qiu
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Yang
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China. wqchen@whu.edu.cn.|State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China. wqchen@whu.edu.cn.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Chen
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.|State Key Laboratory of Microbial Metabolism, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Zixin
authors.initials: Z
authors.lastname: Deng
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism*; D060847:Metabolic Engineering / Q000379:methods*; D019906:Nuclear Magnetic Resonance, Biomolecular; D011741:Pyrimidine Nucleosides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013302:Streptomyces / Q000378:metabolism; D058615:Synthetic Biology
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D011741:Pyrimidine Nucleosides; C002457:polyoxin; C011952:nikkomycin
keywords: Streptomyces aureochromogenes; designer nucleoside antibiotics; nikkomycin; peptidyl nucleoside antibiotics; synthetic biology; the polyoxin producer