Synthesis of Omphalotin A and familiar Secundary Metabolites

The production of new antibiotics based on cyclodepsipeptides (CDPs) is known to be problematic on an industrial scale. Their synthesis can be optimized by using fungal expression systems. Omphalotin A, a product of particular interest here, shows strong and selective activity against plant pathogenic nematodes. The fungal, ribosomally synthesized and posttranslationally modified peptide (RiPP) offers the possibility of further investigation of this hitherto unexplored field. In addition, Omphalotin A shows the peculiarity of N-methylations in the peptide backbone, a structural property previously only known for non-ribosomal peptides.

The invention presented here involves the synthesis of Omphalotin A and its modified secondary metabolites in fungal host organisms (Genera Aspergillus, Penicillium, and Yeast). The necessary enzymes were identified and modified by the introduction of altered gene sequences (synthetic or by PCR). This allows the selective production of either natural or modified Omphalotins. The advantages of this method are the possibility of fed-batch cultivation in a bioreactor using a genetically modified host organism and optimized metabolism independent expression. This enables satisfactory metabolite yields with high purity, including the production of linear N-methylated peptides.