Exploring Structure-Activity Relationships in Synthetic Antimicrobial Peptides (synAMPs) by a Ferrocene Scan

Synthetic antimicrobial peptides (SynAMPs) are an interesting class of novel antibiotic agents used to fight infections caused by resistant bacterial strains. Herein we report the synthesis of a ferrocene-containing lysine (FcLys) suitable for standard Fmoc/tBu solid-phase peptide synthesis. A library of (Arg-Trp)(3)-based antimicrobial peptides have been synthesized in which all the tryptophan residues were replaced systematically by FcLys and their biological activities evaluated. We call this technique a "ferrocene scan", in analogy with the well-established "alanine scan" used to investigate crucial interactions in peptides. The FcLys-peptides showed excellent activity against gram-positive bacterial strains compared with the metal-free parent peptide, including a four-fold increase in activity against the resistant bacterial strain MRSA. Moreover, some members of this family of ferrocenoyl peptides also showed an up to 16-fold increased activity compared with the parent peptide against the gram-negative bacterium A. baumannii. This behavior distinguishes these synAMPs from the previously investigated N-terminally ferrocenoylated peptides, which in general showed a dramatically reduced activity against gram-negative bacteria. The FcLys-peptides also showed low hemolytic activity against red blood cells (RBCs), which indicates excellent bacterial selectivity, making them an attractive class of novel peptide-based organometallic antimicrobial agents.