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From soil to biomanufacturing: Systems-driven metabolic pathway rewiring in non-model bacteria for gram-scale antibiotic production.

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Title: From soil to biomanufacturing: Systems-driven metabolic pathway rewiring in non-model bacteria for gram-scale antibiotic production.
Authors: Cheng, Tingfeng1,2,3 (AUTHOR), Yan, Suihao1,4 (AUTHOR), Xu, Min1,2,3,5 (AUTHOR) xumin@tib.cas.cn, Zhao, Lei1,2,3 (AUTHOR) zhaol@tib.cas.cn
Source: Metabolic Engineering. Jan2026, Vol. 93, p271-285. 15p.
Subjects: Antibiotic synthesis, Natural products, Biochemical engineering, CRISPRs, Bioengineering, Microbial ecology, Multiomics, Fermentation products industry
Abstract: Microbial natural products (NPs) are a pivotal reservoir for drugs used in human health and agriculture. Andrimid, a polyketide-non-ribosomal peptide hybrid antibiotic inhibiting bacterial acetyl-CoA carboxylase, shows enormous potential in antibiotic drug development to mitigate antimicrobial resistance. However, industrial-scale manufacturing and downstream development of andrimid are largely prohibited due to its milligram level production in microorganisms. Herein, using an integrative multi-omics approach, we improved the yield of andrimid remarkably from milligram to gram level in a non-model environmental soil bacterium, Erwinia persicina BST187, isolated from the rhizosphere of tomato. Systematic reprogramming of the pathways for carbon source uptake, competing metabolites biosynthesis, supply of essential building blocks including phenylalanine, glycine, valine and malonyl-CoA and cofactor biosynthesis using CRIPSR/Cas9 based gene editing tools, coupled with fine-tuning the transcription of the biosynthetic genes of andrimid, resulted in the generation of the optimal producer, G17. Combined with fermentation optimization, andrimid was produced to a highest level of 1099.42 mg/L with a productivity of 15.3 mg/L/h using a 5 L bioreactor, representing a 628-fold increase compared to the parental strain. This study showcases the genome wide engineering of non-model bacteria and generates a plasmid- and inducer-free E. persicina strain for high-level andrimid production, providing a blueprint for systems-driven metabolic engineering of complex bioactive NPs for biomanufacturing. [Display omitted] • Multiple metabolic bottlenecks were identified for andrimid biosynthesis in E. persicina BST187. • Constructed an optimal producer, G17, for industrial scale fermentation of andrimid. • Demonstrate the capability of developing non-model bacteria for biomanufacturing of complex bioactive NPs. • The highest reported titer of andrimid (1.10 g/L). [ABSTRACT FROM AUTHOR]
Copyright of Metabolic Engineering is the property of Academic Press Inc. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Label: Title
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  Data: From soil to biomanufacturing: Systems-driven metabolic pathway rewiring in non-model bacteria for gram-scale antibiotic production.
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  Data: <searchLink fieldCode="AR" term="%22Cheng%2C+Tingfeng%22">Cheng, Tingfeng</searchLink><relatesTo>1,2,3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Yan%2C+Suihao%22">Yan, Suihao</searchLink><relatesTo>1,4</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Xu%2C+Min%22">Xu, Min</searchLink><relatesTo>1,2,3,5</relatesTo> (AUTHOR)<i> xumin@tib.cas.cn</i><br /><searchLink fieldCode="AR" term="%22Zhao%2C+Lei%22">Zhao, Lei</searchLink><relatesTo>1,2,3</relatesTo> (AUTHOR)<i> zhaol@tib.cas.cn</i>
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  Data: <searchLink fieldCode="JN" term="%22Metabolic+Engineering%22">Metabolic Engineering</searchLink>. Jan2026, Vol. 93, p271-285. 15p.
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  Data: <searchLink fieldCode="DE" term="%22Antibiotic+synthesis%22">Antibiotic synthesis</searchLink><br /><searchLink fieldCode="DE" term="%22Natural+products%22">Natural products</searchLink><br /><searchLink fieldCode="DE" term="%22Biochemical+engineering%22">Biochemical engineering</searchLink><br /><searchLink fieldCode="DE" term="%22CRISPRs%22">CRISPRs</searchLink><br /><searchLink fieldCode="DE" term="%22Bioengineering%22">Bioengineering</searchLink><br /><searchLink fieldCode="DE" term="%22Microbial+ecology%22">Microbial ecology</searchLink><br /><searchLink fieldCode="DE" term="%22Multiomics%22">Multiomics</searchLink><br /><searchLink fieldCode="DE" term="%22Fermentation+products+industry%22">Fermentation products industry</searchLink>
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  Label: Abstract
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  Data: Microbial natural products (NPs) are a pivotal reservoir for drugs used in human health and agriculture. Andrimid, a polyketide-non-ribosomal peptide hybrid antibiotic inhibiting bacterial acetyl-CoA carboxylase, shows enormous potential in antibiotic drug development to mitigate antimicrobial resistance. However, industrial-scale manufacturing and downstream development of andrimid are largely prohibited due to its milligram level production in microorganisms. Herein, using an integrative multi-omics approach, we improved the yield of andrimid remarkably from milligram to gram level in a non-model environmental soil bacterium, Erwinia persicina BST187, isolated from the rhizosphere of tomato. Systematic reprogramming of the pathways for carbon source uptake, competing metabolites biosynthesis, supply of essential building blocks including phenylalanine, glycine, valine and malonyl-CoA and cofactor biosynthesis using CRIPSR/Cas9 based gene editing tools, coupled with fine-tuning the transcription of the biosynthetic genes of andrimid, resulted in the generation of the optimal producer, G17. Combined with fermentation optimization, andrimid was produced to a highest level of 1099.42 mg/L with a productivity of 15.3 mg/L/h using a 5 L bioreactor, representing a 628-fold increase compared to the parental strain. This study showcases the genome wide engineering of non-model bacteria and generates a plasmid- and inducer-free E. persicina strain for high-level andrimid production, providing a blueprint for systems-driven metabolic engineering of complex bioactive NPs for biomanufacturing. [Display omitted] • Multiple metabolic bottlenecks were identified for andrimid biosynthesis in E. persicina BST187. • Constructed an optimal producer, G17, for industrial scale fermentation of andrimid. • Demonstrate the capability of developing non-model bacteria for biomanufacturing of complex bioactive NPs. • The highest reported titer of andrimid (1.10 g/L). [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Metabolic Engineering is the property of Academic Press Inc. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
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    Identifiers:
      – Type: doi
        Value: 10.1016/j.ymben.2025.11.001
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 15
        StartPage: 271
    Subjects:
      – SubjectFull: Antibiotic synthesis
        Type: general
      – SubjectFull: Natural products
        Type: general
      – SubjectFull: Biochemical engineering
        Type: general
      – SubjectFull: CRISPRs
        Type: general
      – SubjectFull: Bioengineering
        Type: general
      – SubjectFull: Microbial ecology
        Type: general
      – SubjectFull: Multiomics
        Type: general
      – SubjectFull: Fermentation products industry
        Type: general
    Titles:
      – TitleFull: From soil to biomanufacturing: Systems-driven metabolic pathway rewiring in non-model bacteria for gram-scale antibiotic production.
        Type: main
  BibRelationships:
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          Name:
            NameFull: Cheng, Tingfeng
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            NameFull: Yan, Suihao
      – PersonEntity:
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            NameFull: Xu, Min
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            NameFull: Zhao, Lei
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          Dates:
            – D: 01
              M: 01
              Text: Jan2026
              Type: published
              Y: 2026
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            – Type: issn-print
              Value: 10967176
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              Value: 93
          Titles:
            – TitleFull: Metabolic Engineering
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