Biotechnology and Bioprocess Engineering 2021; 26(6): 887-897  
Increasing Demeclocycline Production in Streptomyces aureofaciens by Manipulating the Expression of a Novel SARP Family Regulator and Its Genes
Yan-Ying Tan, Guang-Yao Zhu, Rui-Fang Ye, Hong-Zhou Zhang, and De-Yu Zhu
Yan-Ying Tan, Guang-Yao Zhu, Rui-Fang Ye*
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
Tel/Fax: +86-21-64253286
E-mail: rfye@ecust.edu.cn
Hong-Zhou Zhang, De-Yu Zhu
Topfond Pharmaceutical Co., Ltd, Henan, China
Received: September 3, 2020; Revised: March 9, 2021; Accepted: March 14, 2021; Published online: December 31, 2021.
© The Korean Society for Biotechnology and Bioengineering. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Demeclocycline (DMCTC), a tetracycline derivative antibiotic produced by Streptomyces aureofaciens, has attracted attention owing to its high bioavailability, prolonged maintenance of a therapeutic concentration, and greater efficacy against many infectious microorganisms. However, the productivity of the DMCTC-producing strains has remained low. Thus, it is necessary to identify gene-knockout or amplification targets to increase DMCTC production. Here, we demonstrated that ctcB, which encodes a Streptomyces antibiotic regulatory protein (SARP), and ctcC, which encodes a resistance gene, positively regulate the biosynthesis of DMCTC in S. aureofaciens strain DT1. In particular, overexpression of the ctcB gene in S. aureofaciens DT1 significantly enhanced DMCTC production, resulting in increased expression of ctcG, ctcN, ctcQ, ctcH, ctcV, and ctcC. The deletion of ctcB dramatically reduced the DMCTC level, implying that CtcB is an activator of DMCTC biosynthesis. Although overexpression of the ctcC, which encodes a ribosomal protection protein, enhancing DMCTC biosynthesis in S. aureofaciens DT1, the improvement was limited compared with that achieved by ctcB overexpression. This is the first study to identify the role of ctcB and ctcC in DMCTC accumulation; these genes may also be ideal candidate targets for facilitating DMCTC production by other Streptomyces strains.
Keywords: demeclocycline, Streptomyces aureofaciens, SARP family regulator, resistance gene


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