Cu-ATCUN type 2 peptide

The Cu-ATCUN derivatives show a two- tothree-fold increase in antimicrobial activity for a variety of microbes, relative to Sub5, withMICs as low as 0.3 ± 0.1 μM toward Enterococcus faecium. Sub5 and the ATCUNderivatives bind both plasmid DNA and 16s A-site rRNA with low micromolar affinity.Native Sub5 and the metallopeptide derivatives were shown to promote damage againstDNA to similar extents in cellular studies against both Escherichia coli and Staphylococcusepidermidis, with an almost threefold higher activity against the latter organism. Liposomeexperiments show that the metallopeptides have a greater affinity for model membranes ofE. coli and S. aureus relative to Sub5, which correlates with their enhanced antimicrobialactivity. Sub5 and the metalloderivatives also display no cytotoxicity toward adult humandermal fibroblasts. Addition of the ATCUN motif conferred the ability to promote lipid oxidation toward E. coli and S.epidermidis and enhanced membrane permeability, as evidenced by the extent of ATP leaked from cellular membranes relativeto Sub5 alone. These data suggest that Cu-ATCUN derivatives inhibit microbes through multiple modes of action, resulting inan enhancement in their overall potency.