Careful investigation of structure-activity relationships may eventually allow design of optimised antimicrobial compounds with high activity and Akt inhibitor minimal side effects [9–15]. Many AMPs fold into an amphipathic structure, and it is believed that this topology enables

pore formation or disintegration of bacterial cell membranes leading to bacterial cell death. The amphipathic properties usually include cationic patches that promote interaction with the anionic bacterial membrane as well as hydrophobic patches that favor integration into the membrane. Since this is the most common mode of action for AMPs there has been an intense focus on their ability to adapt an amphipathic conformation [16, 17]. In particular, design of peptides with

a high propensity to fold into a helical amphipathic conformation Pevonedistat datasheet has attracted considerable interest [13, 18–20]. We have previously described a synthetic approach for design of α-peptide/β-peptoid chimeras possessing a design with alternating N-alkylated β-alanine (β-peptoid) and α-amino acid units (Figure 1). In addition, preliminary investigations showed that such peptidomimetics constitute a novel subclass of proteolytically stable antimicrobial compounds [21–23]. This design displays chiral unnatural β-peptoid residues that appear to contribute with structure-promoting effects and lipophilicity, while strongly cationic properties and intramolecular hydrogen bonding capacity are introduced via the α-amino acids lysine and/or homoarginine [24]. The precise secondary structure

of these chimeras still remains to be elucidated, nevertheless, circular dichroism (CD) spectroscopy clearly indicates Y-27632 2HCl the presence of some degree of secondary structure [22, 23]. Interestingly, a higher degree of secondary structure was found for analogues containing chiral side chains in the β-peptoid units (i.e. compounds 2 and 3 in Figure 1) as compared to chimeras with achiral β-peptoid residues (i.e. compound 1 in Figure 1) [22], but the effect of this on antibacterial activity remains largely unresolved [23]. Figure 1 Chemical structure of the six α-peptide/β-peptoid chimeras The membrane-destabilizing effects of the chimeras have only been investigated in model liposomes prepared from phosphatidylcholine, a phospholipid found predominantly in eukaryotic cells, and several of the chimeras permeabilized such liposomal membranes [24]. Most studies on membrane activity of antimicrobial peptides have in fact been performed on model membranes [25–28] while the effects on cell membranes of viable bacteria have often not been tested. Also, the effect of membrane permeabilization on killing of bacteria has not been tested [27].