Periodic Reporting for period 2 - SYNPEP (Synthetic biology of non-ribosomal peptide synthetases to generate new peptides)
Berichtszeitraum: 2021-04-01 bis 2022-09-30
The ERC Advanced Grant SYNPEP is dedicated towards the engineering/modification of non-ribosomal peptide synthetases (NRPS) for the production of novel and bioactive peptides and related natural products (NPs). NRPS are encoded in most microorganisms where they are responsible for the production of NPs that are even used in the clinic as antibiotics, like penicillins, daptomycin or vancomycin or as other drugs (cephalosporin, bleomycin etc).
Within SYNPEP we apply fast and high-throughput methods to find new NRPS systems in bacteria, activate the underlying biosynthetic gene clusters (BGCs), use the identified NRPS fragments to generate novel peptides based on NRPS engineering approaches and produce these products in amounts sufficient for bioactivity testing and/or chemical modification.
The latter is facilitated by new-to-nature NRPS systems that accept unusual and chemically reactive building blocks for targeted modifications.
Within SYNPEP we continuously develop and improve our NRPS engineering methods that now allow to produce thousands (later millions) of novel peptides. These are then screened for their bioactivity in clinical relevant assays based on microfluidics coupling the bacterial production of these peptides directly to their bioassay.
The ultimate goal is to make NRPS engineering accessible to even non-experts in the field. For commercial application the idea is to start a company with a focus on NRPS engineering.
Within SYNPEP we apply fast and high-throughput methods to find new NRPS systems in bacteria, activate the underlying biosynthetic gene clusters (BGCs), use the identified NRPS fragments to generate novel peptides based on NRPS engineering approaches and produce these products in amounts sufficient for bioactivity testing and/or chemical modification.
The latter is facilitated by new-to-nature NRPS systems that accept unusual and chemically reactive building blocks for targeted modifications.
Within SYNPEP we continuously develop and improve our NRPS engineering methods that now allow to produce thousands (later millions) of novel peptides. These are then screened for their bioactivity in clinical relevant assays based on microfluidics coupling the bacterial production of these peptides directly to their bioassay.
The ultimate goal is to make NRPS engineering accessible to even non-experts in the field. For commercial application the idea is to start a company with a focus on NRPS engineering.
Several novel natural products have been identified, >2500 peptides have been produced and screened for bioactivity leading to the identification of bioactive hits. Novel NRPS engineering methods/rules have been developed including the simple combination of 2-3 natural NRPS fragments connected by synthetic docking domains called SYNZIPs that allow a fast and combinatorial generation of new-to-nature peptides. The Myria Biosciences AG, founded in 2021 as a spin-off from scientists of the Goethe Universität Frankfurt and the ETH Zurich dedicated to NRPS engineering and high-throughput screening, is now in full operation.
SYNPEP is perfectly in time with all its goals. Currently one patent and 11 publications have been published (two so far only as preprint in bioRxiv). Until the end of the project we anticipate 2 patents, >25 publications, a new and easy to use NRPS engineering pipeline for everyone and the production of several bioactive peptides that might be developed further with partners from the pharmaceutical industry.