Metabolic engineering of an industrial polyoxin producer for the targeted overproduction of designer nucleoside antibiotics

  • Biotechnol Bioeng. 2015 Sep;112(9):1865-71. doi: 10.1002/bit.25594.
Jianzhao Qi  1 ,  Jin Liu  1 ,  Dan Wan  1 ,  You-Sheng Cai  1 ,  Yinghu Wang  1 ,  Shunying Li  1 ,  Pan Wu  1 ,  Xuan Feng  1 ,  Guofu Qiu  1 ,  Sheng-Ping Yang  1 ,  Wenqing Chen  2  3 ,  Zixin Deng  1  4
Affiliations
  • 1. Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
  • 2. Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China. [email protected].
  • 3. State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China. [email protected].
  • 4. State Key Laboratory of Microbial Metabolism, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200030, China.
PMID: 25827606 DOI: 10.1002/bit.25594
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.

Keywords
Streptomyces aureochromogenes; designer nucleoside antibiotics; nikkomycin; peptidyl nucleoside antibiotics; synthetic biology; the polyoxin producer.
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