Novel remedies in the battle against multidrug-resistant bacterial strains are urgently needed, and one obvious approach involves antimicrobial peptides and mimics hereof. The impact of α- and β-peptoid as well as β(3)-amino acid modifications on the activity profile against β-lactamase-producing Escherichia coli was assessed by testing an array comprising different types of cationic peptidomimetics obtained by a general monomer-based solid-phase synthesis protocol. Most of the peptidomimetics possessed high to moderate activity toward multidrug-resistant E. coli as opposed to the corresponding inactive peptides. Nevertheless, differences in hemolytic activities indicate that a careful choice of backbone design constitutes a significant parameter in the search for effective cationic antimicrobial peptidomimetics targeting specific bacteria.

Infections with multidrug-resistant pathogens are an increasing concern for public health. Recently, subtypes of peptide-peptoid hybrids were demonstrated to display potent activity against multidrug-resistant Gram-negative bacteria. Here, structural variation of these antibacterial peptidomimetics was investigated as a tool for optimizing cell selectivity. A protocol based on dimeric building blocks allowed for efficient synthesis of an array of peptide-peptoid oligomers representing length variation as well as different backbone designs displaying chiral or achiral peptoid residues. Lack of α-chirality in the side chains of the peptoid residues proved to be correlated to reduced cytotoxicity. Furthermore, optimization of the length of these peptidomimetics with an alternating cationic-hydrophobic design was a powerful tool to enhance the selectivity against Gram-negative pathogens over benign mammalian cells. Thus, lead compounds with a high selectivity toward killing of clinically important multidrug-resistant E. coli were identified.

The in vitro activity of a host defense peptidomimetic (HDM-4) was investigated. The compound exhibited an antimicrobial activity profile against a range of Gram-negative bacteria. HDM-4 permeabilized the outer membrane and partly depolarized the inner membrane at its minimal inhibitory concentration (MIC). Moreover, it was demonstrated that HDM-4 was distributed widely in the bacterial cell at lethal concentrations, and that it could bind to DNA. It was confirmed that the multimodal action of HDM-4 resulted in it being less likely to lead to resistance development as compared to single-target antibiotics. HDM-4 exhibited multispecies anti-biofilm activity at sub-MIC levels. Furthermore, HDM-4 modulated the immune response by inducing the release of the chemoattractants interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), and MCP-3 from human peripheral blood mononuclear cells. In addition, the compound suppressed lipopolysaccharide-mediated inflammation by reducing the release of the pro-inflammatory cytokines IL-6 and tumor necrosis factor-α.

No abstract