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Engineered biosynthesis and characterization of disaccharide-pimaricin

Summary

Scientists engineered a bacterium to produce a modified antibiotic called disaccharide-pimaricin that fights fungal infections with much better safety. This new compound dissolves better in water (107 times more soluble) and is much less toxic to human blood cells (12.6 times safer) compared to regular pimaricin, while still maintaining antifungal effectiveness. Through optimized fermentation processes, they achieved high production yields of 138 mg/L, making this a promising candidate for safer antifungal treatments.

Background

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

Objective

To engineer Streptomyces gilvosporeus capable of producing disaccharide-pimaricin through heterologous expression of the nppY gene encoding a glycosyltransferase, and to characterize the novel compound’s structure and properties.

Results

Disaccharide-pimaricin was successfully produced with a mycosaminyl-α1–4-N-acetylglucosamine moiety. DSP showed 50% reduction in antifungal activity, 12.6-fold decrease in hemolytic toxicity, and 107.6-fold increase in water solubility compared to pimaricin. Maximum DSP titer of 138.168 mg/L was achieved with optimized fermentation conditions at 28°C for 108 hours.

Conclusion

This study demonstrates the potential of disaccharide polyene macrolides as safer antifungal agents with significantly improved water solubility and reduced toxicity. The engineered strain and optimized fermentation protocol provide a framework for producing next-generation polyene antibiotics with enhanced therapeutic properties and reduced hemolytic side effects.
  • Published in:Microbial Cell Factories,
  • Study Type:Experimental Research,
  • Source: PMID: 40405243, DOI: 10.1186/s12934-025-02742-9
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