Proteolytically Stable Foldamer Mimics of Host-Defense Peptides with Protective Activities in a Murine Model of Bacterial Infection

The synthesis of bioinspired unnatural backbones leading to foldamers can provide effective peptide mimics with improved properties in a physiological environment. This approach has been applied to the design of structural mimics of membrane active antimicrobial peptides (AMPs) for which activities <i>in vitro</i> have been reported. Yet activities and pharmacokinetic properties <i>in vivo</i> in animal models have remained largely unexplored. Here, we report helical oligourea AMP mimics that are active <i>in vitro</i> against bacterial forms of <i>Bacillus anthracis</i> encountered <i>in vivo</i>, as well as <i>in vivo</i> in inhalational and cutaneous mouse models of <i>B. anthracis</i> infection. The pharmacokinetic profile and the tissue distribution were investigated by β-radio imager whole-body mapping in mice. Low excretion and recovery of the native oligourea in the kidney following intravenous injection is consistent with high stability <i>in vivo</i>. Overall these results provide useful information that support future biomedical development of urea-based foldamer peptide mimics