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Combined transcriptomic and pangenomic analyses guide metabolic amelioration to enhance tiancimycins production.
Lin, Jing; Xiao, Yu; Liu, Huiming; Gao, Die; Duan, Yanwen; Zhu, Xiangcheng.
Afiliación
  • Lin J; Xiangya International Academy of Translational Medicine, Central South University, Yuelu District, Tongzipo Road, #172, Changsha, 410013, Hunan, China.
  • Xiao Y; Xiangya International Academy of Translational Medicine, Central South University, Yuelu District, Tongzipo Road, #172, Changsha, 410013, Hunan, China.
  • Liu H; Xiangya International Academy of Translational Medicine, Central South University, Yuelu District, Tongzipo Road, #172, Changsha, 410013, Hunan, China.
  • Gao D; Xiangya International Academy of Translational Medicine, Central South University, Yuelu District, Tongzipo Road, #172, Changsha, 410013, Hunan, China.
  • Duan Y; Xiangya International Academy of Translational Medicine, Central South University, Yuelu District, Tongzipo Road, #172, Changsha, 410013, Hunan, China. ywduan66@sina.com.
  • Zhu X; Hunan Engineering Research Center of Combinatorial Biosynthesis and Natural Product Drug Discovery, National Engineering Research Center of Combinatorial Biosynthesis for Drug Discovery, Changsha, 410013, Hunan, China. ywduan66@sina.com.
Appl Microbiol Biotechnol ; 108(1): 18, 2024 Dec.
Article en En | MEDLINE | ID: mdl-38170317
ABSTRACT
Exploration of high-yield mechanism is important for further titer improvement of valuable antibiotics, but how to achieve this goal is challenging. Tiancimycins (TNMs) are anthraquinone-fused enediynes with promising drug development potentials, but their prospective applications are limited by low titers. This work aimed to explore the intrinsic high-yield mechanism in previously obtained TNMs high-producing strain Streptomyces sp. CB03234-S for the further titer amelioration of TNMs. First, the typical ribosomal RpsL(K43N) mutation in CB03234-S was validated to be merely responsible for the streptomycin resistance but not the titer improvement of TNMs. Subsequently, the combined transcriptomic, pan-genomic and KEGG analyses revealed that the significant changes in the carbon and amino acid metabolisms could reinforce the metabolic fluxes of key CoA precursors, and thus prompted the overproduction of TNMs in CB03234-S. Moreover, fatty acid metabolism was considered to exert adverse effects on the biosynthesis of TNMs by shunting and reducing the accumulation of CoA precursors. Therefore, different combinations of relevant genes were respectively overexpressed in CB03234-S to strengthen fatty acid degradation. The resulting mutants all showed the enhanced production of TNMs. Among them, the overexpression of fadD, a key gene responsible for the first step of fatty acid degradation, achieved the highest 21.7 ± 1.1 mg/L TNMs with a 63.2% titer improvement. Our studies suggested that comprehensive bioinformatic analyses are effective to explore metabolic changes and guide rational metabolic reconstitution for further titer improvement of target products. KEY POINTS • Comprehensive bioinformatic analyses effectively reveal primary metabolic changes. • Primary metabolic changes cause precursor enrichment to enhance TNMs production. • Strengthening of fatty acid degradation further improves the titer of TNMs.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Streptomyces / Antibacterianos Idioma: En Revista: Appl Microbiol Biotechnol Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Alemania
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Streptomyces / Antibacterianos Idioma: En Revista: Appl Microbiol Biotechnol Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Alemania