ArticleApplied microbiology and biotechnology2026
Co-cultivation Serratia marcescens with Trichoderma harzianum for improving production of Huperzine A.
Article in Applied microbiology and biotechnology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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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.
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