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

摘要

A new solid-phase peptide synthesis and bioprofiling of the antimicrobial activity of lugdunin, a fibupeptide, enable a comprehensive structure-activity relationship (SAR) study (MRSA Staphylococcus aureus). Distinct lugdunin analogues with variation of the three important amino acids Val(2), Trp(3), and Leu(4) are readily available based on the established high-output synthesis. This efficient synthesis concept takes advantage of the presynthesized thiazolidine building block. To gain further knowledge of SAR, D-Val(2), and D-Leu(4) were replaced with aliphatic amino acids. For L-Trp(3) derivatization, a set of non-natural aromatic amino acids with manifold substitution and annulation patterns precisely shows structural imperatives, starting from the exchange of D-Val(6). D-Trp(6) with a 2-fold improved biological activity. D-Trp(6)-lugdunin analogues with additional variation of D-Val(2) and D-Leu(4) residues were designed and synthesized followed by antimicrobial profiling. For the first time, these SAR studies deliver valuable information on the tolerance of other amino acids to D-Val(2), L-Trp(3), and D-Leu(4) in the sequence of lugdunin.