6b35

Publication Abstract from PubMed

The d-Phe-Pro beta-turn of the cyclic beta-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 beta-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 beta-hairpin libraries. Unlike traditional beta-turn motifs such as d-Pro-Gly, both the 2-Abz and d-Phe rings may be further functionalized.

Tyrocidine A Analogues Bearing the Planar d-Phe-2-Abz Turn Motif: How Conformation Impacts Bioactivity.,Cameron AJ, Edwards PJB, Harjes E, Sarojini V J Med Chem. 2017 Nov 28. doi: 10.1021/acs.jmedchem.7b00953. PMID:29140694^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.