Many peptide-based natural products of therapeutic importance are synthesised by non-ribosomal peptide synthetases (NRPSs). Our objective is to expand the scope of one of these natural systems of combinatorial chemistry, tyrocidine synthetase, by directed evolution. We will re-programme this biosynthetic route by using (and further developing) a new in vitro evolution system, GENESCIS. By applying in vitro mutagenesis and selection, we will evolve novel stand-alone modules or functional chimeras with relax ed or altered specificity that will be tested for their ability to make useful quantities of peptide product. This work is expected not only to generate novel NRPSs but also to enrich our knowledge as to how these multi-enzyme complexes work.
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