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

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 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.