Infection diseases caused by antibiotic resistant bacteria, especially MRSA (methicillin resistant staphylococcus aureus), remain a rising concern. Thiazolidine containing cyclopeptide Lugdunin, which was discovered in 2016, shows a promising antibiotic activity against MRSA. The structure was elucidated via NMR spectroscopy and mass spectrometry. In cooperation with our partners in Microbiology Tübingen, biosynthesis was resolved. A sythesis strategy via SPPS (solid phase peptide synthesis) was established, leading the way to broad research on biological activity.

Human commensals producing a novel antibiotic impair pathogen colonization.

Via SPPS, more than 50 derivatives were synthesized in a short time in order to investigate structure-activity relationship. Thus, we found the novel thiazolidine structure and the D/L alternating configuration to be essential for biological activity. Furthermore, after build-in of a tryptophane moiety, the MIC (minimal inhibitory concentration) was reduced to half of the original value.

Synthetic Lugdunin Analogues Reveal Essential Structural Motifs for Antimicrobial Action and Proton Translocation Capability

Further optimization of SPPS led to the option to use cheaper and more common resins for the synthesis of lugdunin and its derivatives. Also, diversity was increased by build-in of the non-natural amino acid propargylglycine, leading the way to surface immobilization of the antibiotic.

Distinct Lugdunins from a New Efficient Synthesis and Broad Exploitation of Its MRSA-Antimicrobial Structure