Chemical Society Seminar: Stephanie Grond - Lugdunin - a new antibiotic from our nose: Structure, chemical synthesis and bioactivity

A Staphylococcus lugdunensis isolate from the human nose was found to produce a compound with strong bactericidal activity against multi-resistant Staphylococcus aureus.
The bioactive substance was purified from the extract. Structure elucidation by 1D- and 2D-NMR, high resolution mass spectrometry, multistage tandem mass spectrometry, advanced Marfey’s analysis and tailored colour reactions revealed a mostly hydrophobic cyclic heptapeptide with alternating amino acid stereoconfiguration. The thiazolidine heterocycle – for the first time in a cyclopeptide – and a tryptophan are characteristic for the compounds with potent biological activity.

Named lugdunin A (1), the assigned structure of the main compound was confirmed by chemical synthesis. The solid phase peptide synthesis (SPPS) was especially customized to form the new thiazolidine heterocycle in this cycloheptapeptide. A non-ribosomal peptide synthase (NRPS) is responsible for the biosynthesis in Staphylococcus lugdunensis. With manifold products from our chemical synthesis, the important SAR (structure activity relationship)-studies comprise an alanine scan to assess the significance of individual amino acids for biological activity. The stereo scan emphasized the relevance of the peptide`s backbone D-, L- stereochemistry. Notably, the enantiomer of lugdunin A (1) is as active as lugdunin itself. Therefore, we shuffled the stereocenters and amino acids within the backbone sequence and derivatized lugdunin to reveal nature’s architectural concept of the antibacterial agent.