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

Jianzhao Qi, Jin Liu, Dan Wan, You-Sheng Cai, Yinghu Wang, Shunying Li, Pan Wu, Xuan Feng, Guofu Qiu, Sheng-Ping Yang, Wenqing Chen, Zixin Deng

Biotechnology and bioengineering 2015 Sep

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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. © 2015 Wiley Periodicals, Inc.

Citation

Jianzhao Qi, Jin Liu, Dan Wan, You-Sheng Cai, Yinghu Wang, Shunying Li, Pan Wu, Xuan Feng, Guofu Qiu, Sheng-Ping Yang, Wenqing Chen, Zixin Deng. Metabolic engineering of an industrial polyoxin producer for the targeted overproduction of designer nucleoside antibiotics. Biotechnology and bioengineering. 2015 Sep;112(9):1865-71