Tyrocidine A Analogues Bearing the Planar d‑Phe-2-Abz Turn Motif: How Conformation Impacts Bioactivity

The d-Phe-Pro β-turn
of the cyclic β-hairpin
antimicrobial decapeptide tyrocidine A, (Tyrc A) was substituted with
the d-Phe-2-aminobenzoic acid (2-Abz) motif in a synthetic
analogue (1). The NMR structure of 1 demonstrated
that compound 1 retained the β-hairpin structure
of Tyrc A with additional planarity, resulting in approximately 30-fold
reduced hemolysis than Tyrc A. Although antibacterial activity was partially compromised, a single
Gln to Lys substitution (2) restored activity equivalent
to Tyrc A against S. aureus, enhanced
activity against two Gram negative strains and maintained the reduced
hemeloysis of 1. Analysis by transmission electron microscopy
(TEM) suggested a membrane lytic mechanism of action for these peptides.
Compound 2 also exhibits nanomolar antifungal activity
in synergy with amphotericin B. The d-Phe-2-Abz turn may
serve as a tool for the synthesis of structurally predictable β-hairpin
libraries. Unlike traditional β-turn motifs such as d-Pro-Gly, both the 2-Abz and d-Phe rings may be further
functionalized.