Cyclic peptide natural products are a fantastic source of medicines, including antibiotics and immunosuppressants. Unfortunately, discovering novel cyclic peptides can be an arduous task due to the low expression of many natural product biosynthetic gene clusters and challenging purifications. For this reason, we developed SNaPP (Synthetic Natural Product Inspired Cyclic Peptides). SNaPP expedites bioactive molecule discovery by combining bioinformatics predictions of non-ribosomal peptide synthetases with chemical synthesis of the predicted natural products (pNPs). Head-to-tail cyclic peptides were targeted by using a recently discovered cyclase, the penicillin binding protein-like cyclase, as the initial search input.  Analysis of 500 biosynthetic gene clusters allowed for identification of 131 novel pNPs. 51 diverse pNPs were synthesized using solid phase peptide synthesis and solution-phase cyclization. Antibacterial testing revealed 14 pNPs with antibiotic activity, including activity against multidrug-resistant Gram-negative bacteria. Overall, SNaPP demonstrates the power of combining bioinformatics predictions with chemical synthesis to accelerate the discovery of bioactive molecules. Additionally, SNaPP allowed for identification of PBP-like cyclases potentially capable of performing challenging cyclizations, such as for tetrapeptides. We have experimentally confirmed these activities and found one enzyme with a greatly expanded substrate scope that could have great utility as a biocatalyst.

Synthetic natural product inspired cyclic peptides for discovery of bioactive natural products and biocatalysts

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.