Harnessing the diversity of ATP grasp-type depsipeptide biosyntheses in cyanobacteria: genomic mining and engineering

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Natural product-based drug development in the last century was largely focussing on four groups of compounds: terpenoids, alkaloids, polyketides and non-ribosomal peptides. In the past few years, another group of metabolites, ribosomally produced and posttranslationally modified peptides (RiPPs) attracted increasing attention. We have recently shown the great engineering potential of microviridin for the optimization against different serine type proteases. The limitation of the system, however, is the low promiscuity in the ring size of the peptides. In the present project, we therefore aim to analyze further ATPgrasp type RiPP biosyntheses from cyanobacteria for which we anticipate alternative ring sizes. Specifically, we intend to identify the peptides by using different genomic mining strategies. We further aim to understand the mechanistic basis that determines the ring size and the specific role of the leader peptide. We will evaluate the potential of at least one novel ATPgrasp type RiPP for rational and random engineering approaches. Finally, we will assess the bioactivity of the novel peptides and plan to develop a high throughput screening system via phage display. The overarching aim of the study is to develop a platform for the tailor-made design of cyclic depsipeptides of different ring sizes that can potentially be screened against diverse targets.