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

Abstract

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 <i>Staphylococcus aureus</i>). Distinct lugdunin analogues with variation of the three important amino acids Val², Trp³, and Leu⁴ 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-Val², and d-Leu⁴ were replaced with aliphatic amino acids. For l-Trp³ 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-Val⁶ → d-Trp⁶ with a 2-fold improved biological activity. d-Trp⁶-lugdunin analogues with additional variation of d-Val² and d-Leu⁴ 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-Val², l-Trp³, and d-Leu⁴ in the sequence of lugdunin.