MarR family regulator LcbR2 activates lincomycin biosynthesis in multiple ways

Ruida Wang; Lei Chen; Jiaqi Zhao; Yu Gao; Tianyu Zhou; Jiang Ye; Haizhen Wu; Huizhan Zhang

doi:10.1016/j.ijbiomac.2025.140292

MarR family regulator LcbR2 activates lincomycin biosynthesis in multiple ways

Int J Biol Macromol. 2025 Apr:300:140292. doi: 10.1016/j.ijbiomac.2025.140292. Epub 2025 Jan 23.

Authors

Ruida Wang¹, Lei Chen², Jiaqi Zhao², Yu Gao², Tianyu Zhou², Jiang Ye³, Haizhen Wu⁴, Huizhan Zhang⁵

Affiliations

¹ Department of Applied Biology, School of Biotechnology, East China University of Science and Technology, Shanghai 200237, China; State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China; College of Life Science and Technology, Tarim University, Alar 843300, China.
² Department of Applied Biology, School of Biotechnology, East China University of Science and Technology, Shanghai 200237, China; State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China.
³ Department of Applied Biology, School of Biotechnology, East China University of Science and Technology, Shanghai 200237, China. Electronic address: yyjj413@163.com.
⁴ Department of Applied Biology, School of Biotechnology, East China University of Science and Technology, Shanghai 200237, China; State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China. Electronic address: wuhzh@ecust.edu.cn.
⁵ Department of Applied Biology, School of Biotechnology, East China University of Science and Technology, Shanghai 200237, China.

PMID: 39863210
DOI: 10.1016/j.ijbiomac.2025.140292

Abstract

Lincomycin, produced by the actinomycete Streptomyces lincolnensis, is highly effective against Gram-positive bacteria and protozoans, making it widely used in clinical settings. This study identified LcbR2, a MarR family transcriptional regulator, as an activator of lincomycin biosynthesis. Knocking out the lcbR2 gene reduced lincomycin production by 63.0 % without affecting growth or morphology. Quantitative real-time PCR, electrophoretic mobility shift assays, and XylE reporter assays demonstrated that LcbR2 binds to a 13-bp imperfect palindromic sequence -TTGCCnnnnnCAA-, repressing the expression of lcbR2 Further analysis revealed that LcbR2 directly activates the expression of lincomycin biosynthesis genes (lmbD, lmbJ, lmbK, lmbV, and lmbW), enhancing lincomycin production. It also regulates lincomycin resistance genes (lmrA and lmrB), increasing the self-tolerance of S. lincolnensis to lincomycin. Additionally, LcbR2 modulates other regulatory genes (lmbU, adpA, aflQ1, bldD, and lcbR1), affecting lincomycin production in a cascade manner. LcbR2 also influences the expression of genes related to carbon, nitrogen, phosphorus, and sulfur metabolism, indirectly impacting lincomycin production. Moreover, the binding of LcbR2 to DNA can be attenuated by apramycin. This study thus characterized LcbR2 as a novel transcriptional regulator with a broad regulatory scope.

Keywords: LcbR2; Lincomycin biosynthesis; MarR family; Streptomyces lincolnensis; Transcriptional regulator.

MeSH terms

Bacterial Proteins* / genetics
Bacterial Proteins* / metabolism
Gene Expression Regulation, Bacterial* / drug effects
Lincomycin* / biosynthesis
Lincomycin* / pharmacology
Streptomyces* / genetics
Streptomyces* / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

Lincomycin
Bacterial Proteins
Transcription Factors

Supplementary concepts

Streptomyces lincolnensis