Out-licensing

Methods of Producing Validienamycin Analogues

Introduction/Background

The antifungal agent validamycin A is an important crop protectant and the source of valienamine, the precursor of the antidiabetic drug voglibose.

Aims/Hypothesis

Our research is focused on the development of a novel method of producing validamycin A analogues.

Research

Inactivation of the valN gene in the validamycin A producer, Streptomyces hygroscopicus subsp. jinggangensis 5008, resulted in a mutant strain that produces new secondary metabolites 1,1'-bis-valienamine and validienamycin. The chemical structures of 1,1'-bis-valienamine and validienamycin were elucidated by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy in conjunction with mass spectrometry and bioconversion employing a glycosyltransferase enzyme, ValG. 1,1'-Bis-valienamine and validienamycin exhibit a moderate antifungal activity against Pellicularia sasakii. Chemical degradation of 1,1'-bis-valienamine using N-bromosuccinimide followed by purification of the products with ion-exchange column chromatography only resulted in valienamine, whereas parallel treatments of validoxylamine A, the aglycon of validamycin A, resulted in an approximately 1:1 mixture of valienamine and validamine, underscoring the advantage of 1,1'-bis-valienamine over validoxylamine A as a commercial source of valienamine.

Conclusion

This invention is a method of producing validamycin A analogues and biosynthesis and their potential use. The invention further relates to the use of validamycin biosynthetic gene valN knock-out mutant strains to produce validamycin analogues which could be used as drugs and drug precursors for uses in humans, animals and plants as antifungal agents.

Relevance/Opportunity

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Registered

US Patent pending