Synthesis of Omphalotin A and familiar secondary metabolites

The production of new antibiotics based on cyclodepsipeptides (CDPs) is known to be problematic on an industrial scale. (A depsipeptide is a peptide in which one or more of its amide, -C(O)NHR-, groups are replaced by the corresponding ester, -C(O)OR.) Many depsipeptides have both peptide and ester linkages and 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 of a Berlin-based university 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 - polymerase chain reaction). 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. (A fed-batch is an operational technique where one or more nutrients are fed to the bioreactor during cultivation and in which the products remain in the bioreactor until the end of the process.) This enables satisfactory metabolite yields with high purity, including the production of linear N-methylated peptides. The university is interested in a cooperation in the framework of a license agreement or a research cooperation agreement. A future licensee would have the authorization to use the synthesis method in return for a fee or a share of royalties. The client would also agree to a research cooperation agreement which leads to further optimisation of the method to enable a large scale production process.