ERC Advanced Grant SYNPEP

Synthetic Biology of non-ribosomal peptide synthetases to generate new peptides, 835108

01.10.2019 - 30.09.2024

Overview

The ERC Advanced Grant SYNPEP was 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 (cyclosporin, bleomycin etc).
Within SYNPEP we developed 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 developed and improved our NRPS engineering methods that now allow to produce thousands of novel peptides. These are then screened for their bioactivity in clinical relevant assays. Major new NRPS engineering approaches are based on synthetic docking domains (called SYNZIPs) and a new fusion site identified within thiolation (T) domains named XUT approach. The latter approach also allowed the engineering of hybrid enzymes between NRPS and polyketide synthases (PKS) since the T domain is the only shared domain in these very important enzymes for natural product biosynthesis.
The ultimate goal of SYNPEP was to make NRPS engineering accessible to even non-experts in the field. For commercial application, the methods developed within SYNPEP were used to found a company named Myria Biosciences AG.

Dissemination and output

The results of SYNPEP were presented by SYNPEP team members in >30 talks and >30 posters to the scientific audience at national and international conferences. In total 30 publications were generated during SYNPEP until now.
One non-scientific highlight was the performance of how an NRPS works with a group of 20 lab members during the anniversary of the Max-Planck Society in Göttingen in 2023 Link to Video.

Another highlight was the organization of the first Max-Planck Kinder-Uni in 2024, where 2 x 120 school kids (10-12 years old) were introduced to the importance of microbiology, natural products produced by microorganisms, and then went into the Botanical Garden of the Philipps Universität Marburg to collect plant material from which they isolated bacteria showing different pigmented and thus natural product producing bacteria.
 

SYNPEP Publications