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Combining Ribosomal Engineering with Heterologous Expression of a Regulatory Gene to Improve Milbemycin Production in Streptomycesmilbemycinicus A2079

Authors
  • Wang, S.1, 2
  • Lu, F.2
  • Yang, Z.3
  • Li, Z.3
  • Tian, Y.1, 2
  • 1 Key laboratory of Leather Chemistry and Engineering (Sichuan University), Ministry of Education, Chengdu, 610065, P. R. China , Chengdu (China)
  • 2 College of Biomass Science and Engineering, Sichuan University, Chengdu, 610065, P. R. China , Chengdu (China)
  • 3 Chengdu Jinkai Bioengineering Co., Ltd, Chengdu, 611130, P. R. China , Chengdu (China)
Type
Published Article
Journal
Applied Biochemistry and Microbiology
Publisher
Pleiades Publishing
Publication Date
May 01, 2021
Volume
57
Issue
3
Pages
303–310
Identifiers
DOI: 10.1134/S0003683821030133
Source
Springer Nature
Keywords
License
Yellow

Abstract

AbstractMilbemycin, a group of 16-membered macrolide antibiotics produced by Streptomyces milbemycinicus, has been widely used as an insecticide and an anthelmintic. To enhance the production of milbemycin, ribosomal engineering with heterologous expression of a regulatory gene was used to screen for a high milbemycin-producing mutant. The mutant S. milbemycinicus R2-6-5 isolated after the treatment of S. milbemycinicus A2079 with 6 μg/mL streptomycin produced 172.5 and 163.1% of milbemycins A3 and A4, respectively, compared with original strain. Analysis of the gene rsmG revealed a frameshift mutation, one cytidine unit being inserted into the 21 position (21C → 21CC). The heterologous regulatory gene aveR, which belongs to the LAL-family was integrated into the genome of S. milbemycinicus R2-6-5 denoted S. milbemycinicus J37 to enhance production of milbemycin. The production of milbemycins A3 and A4 in S. milbemycinicus J37 reached 758.9 and 279.0 μg/g respectively, representing 142 and 61% higher yields over S. milbemycinicus R2-6-5. The combination of ribosomal engineering and heterologous regulatory gene expression in S. milbemycinicus J37 resulted in an increase by 12.4-fold for milbemycin A3 and 11.7-fold for milbemycin A4, respectively, when compared to the original strain. Overall, these results demonstrate that combining available technologies for strain modification such as ribosome engineering technology and heterologous regulatory gene expression is an effective approach for development of high milbemycin-producing strains.

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