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Engineered biosynthesis and characterization of disaccharide-pimaricin

Summary

Scientists successfully created a genetically engineered bacterium that produces a safer version of an antifungal drug called pimaricin. The new version, called disaccharide-pimaricin, dissolves much better in water and causes significantly less damage to human blood cells, making it a much safer option for treating fungal infections. Although it’s slightly less effective at killing fungi, the improvement in safety and solubility makes it a promising candidate for treating eye infections and other fungal diseases.

Background

Polyene macrolides are potent antifungal agents but exhibit significant hemolytic toxicity due to cross-reactivity with mammalian cell membranes. Disaccharide polyene macrolides have been shown to possess superior water solubility and reduced toxicity compared to monosaccharide counterparts, making them promising candidates for safer antifungal therapeutics.

Objective

This study aimed to engineer Streptomyces gilvosporeus through heterologous expression of the nppY gene to produce disaccharide-pimaricin (DSP), characterize its structure and biological properties, and optimize fermentation conditions for improved yield.

Results

The engineered strain successfully produced disaccharide-pimaricin with a unique disaccharide moiety (mycosaminyl-α1–4-N-acetylglucosamine). DSP demonstrated 50% reduction in antifungal activity but 12.6-fold decrease in hemolytic toxicity and 107.6-fold increase in water solubility compared to pimaricin. Optimized fermentation conditions achieved a maximum DSP titer of 138.168 mg/L with 38% conversion efficiency from pimaricin.

Conclusion

This study successfully engineered S. gilvosporeus to produce disaccharide-pimaricin, demonstrating the therapeutic potential of disaccharide-modified polyene macrolides as safer antifungal agents. The established framework for strain engineering, fermentation optimization, and purification protocols provides critical insights for developing next-generation polyene antibiotics with improved safety profiles.
  • Published in:Microbial Cell Factories,
  • Study Type:Experimental Study,
  • Source: PMID: 40405243, DOI: 10.1186/s12934-025-02742-9
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