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Abstract <p>Plant-derived (−)-Huperzine A (HupA), the bioactive enantiomer of the acetylcholinesterase inhibitor used for Alzheimer’s disease (AD) therapy, is limited by the scarcity of <i>Huperzia</i> <i>serrata</i> (<i>HS</i>), while chemically synthesized (+)-HupA is clinically unviable due to high toxicity and low activity (1/30 that of (−)-HupA), creating a critical bottleneck for HupA pharmaceutical development that necessitates microbial biosynthesis solutions. In this study, we isolated the endophytic bacterium <i>Serratia marcescens</i> HL-1 from <i>HS</i> (identified via morphological characterization and 16S rRNA sequencing) and developed a novel co-cultivation strategy with <i>Trichoderma</i> <i>harzianum</i> NSW-V in modified PDA medium (26&#xa0;°C, 2&#xa0;days): This co-cultivation system sustained the stable HupA biosynthetic capacity of both <i>Serratia marcescens</i> HL-1 and <i>Trichoderma harzianum</i> NSW-V, synergistically enhancing the (−)-HupA yield of the endophytic bacterium to 32.976 ± 0.21&#xa0;mg/L (biosynthetic HupA, BHA) and concurrently boosting the HupA production of the fungal strain; this revealed a positive upward trend in HupA yield with co-cultivation intervention, but no statistically significant differences were observed between groups (<i>p</i> &gt; 0.05), and notably co-cultivation restored the strain’s HupA-synthesizing capacity when its native production potential declined. BHA exhibited physicochemical properties and crystal structure identical to plant-derived (−)-HupA (PHA), as validated by NMR spectroscopy and molecular docking analyses. Furthermore, we identified a novel pharmacological role for HupA: BHA protected pancreatic islet β-cells in a palmitic acid-induced injury model, where cell viability increased from 58.2% to 71.2% (one-way ANOVA followed by Dunnett’s test, <i>p</i> &lt; 0.01, <i>n</i> = 3 independent experiments), revealing an unprecedented role of HupA in pancreatic β-cell protection beyond its well-established anti-AD activity.</p> Key points <p><i>•&#xa0;</i><i>Co-cultivation of endophytic fungi and bacteria could highly express prior HupA. </i></p>

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Co-cultivation Serratia marcescens with Trichoderma harzianum for improving production of Huperzine A

  • 期刊论文

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  • 发表日期：

    2026年3月19日

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  • Han Wen-Xia,
  • Han Zhong-Wen,
  • Mi Yu,
  • Zhang Han,
  • Li Wei-Ze,
  • Guan Li,
  • Zhang Ning,
  • Wang Lin,
  • Jia Min,
  • Mei Shan-Shan

摘要

Abstract

Plant-derived (−)-Huperzine A (HupA), the bioactive enantiomer of the acetylcholinesterase inhibitor used for Alzheimer’s disease (AD) therapy, is limited by the scarcity of Huperzia serrata (HS), while chemically synthesized (+)-HupA is clinically unviable due to high toxicity and low activity (1/30 that of (−)-HupA), creating a critical bottleneck for HupA pharmaceutical development that necessitates microbial biosynthesis solutions. In this study, we isolated the endophytic bacterium Serratia marcescens HL-1 from HS (identified via morphological characterization and 16S rRNA sequencing) and developed a novel co-cultivation strategy with Trichoderma harzianum NSW-V in modified PDA medium (26 °C, 2 days): This co-cultivation system sustained the stable HupA biosynthetic capacity of both Serratia marcescens HL-1 and Trichoderma harzianum NSW-V, synergistically enhancing the (−)-HupA yield of the endophytic bacterium to 32.976 ± 0.21 mg/L (biosynthetic HupA, BHA) and concurrently boosting the HupA production of the fungal strain; this revealed a positive upward trend in HupA yield with co-cultivation intervention, but no statistically significant differences were observed between groups (p > 0.05), and notably co-cultivation restored the strain’s HupA-synthesizing capacity when its native production potential declined. BHA exhibited physicochemical properties and crystal structure identical to plant-derived (−)-HupA (PHA), as validated by NMR spectroscopy and molecular docking analyses. Furthermore, we identified a novel pharmacological role for HupA: BHA protected pancreatic islet β-cells in a palmitic acid-induced injury model, where cell viability increased from 58.2% to 71.2% (one-way ANOVA followed by Dunnett’s test, p < 0.01, n = 3 independent experiments), revealing an unprecedented role of HupA in pancreatic β-cell protection beyond its well-established anti-AD activity.

Key points

• Co-cultivation of endophytic fungi and bacteria could highly express prior HupA.