However, one drawback of most natural AMPs as therapeutics is their susceptibility to proteolytic degradation [6]. To overcome this problem an approach known as peptidomimetics has emerged in recent years by which compounds are produced that mimic a peptide structure and/or function but carries a modified backbone and/or non-natural amino acids. The peptide-mimetic compounds have been designed based on AZD5363 essential biophysical characteristics

of AMPs: charge, hydrophobicity, and amphiphatic organization [7–9]. Oligomeric N-substituted glycines, also known as peptoids, belong to the simpler AMP-mimetic designs. They are structurally similar to α-amino peptides, but the side chain is shifted to amide nitrogen instead

of the α-carbon [10–12]. This feature offers several advantages including protease stability [13], Copanlisib solubility dmso and easy synthesis by the submonomer approach [11]. Previously, a study screening 20 lysine-peptoid hybrids identified a hybrid displaying good antimicrobial activity toward a wide range of clinically relevant bacteria, including Staphylococcus aureus (S. aureus), in addition to low cytotoxicity to mammalian cells [14, 15]. The lysine-peptoid hybrid LP5 (lysine-peptoid compound 5) contains the peptoid core [N-(1-naphthalenemethyl)glycyl]-[N-4-methylbenzyl)glycyl]-[N-(1-naphthalenemethyl)glycyl]-N-(butyl)glycin Vistusertib cell line amide and 5 lysines

(Figure 1) [14, 15]. LP5 is thus potentially interesting as a lead structure in the development of new antimicrobials functioning against pathogens like S. aureus which are increasingly becoming resistant toward conventional antibiotics [16]. Figure 1 Chemical structure of the lysine-peptoid hybrid LP5. Due to their cationic and amphiphatic nature, it is believed that most AMPs selectively kill bacteria by penetrating the negatively charged cell Doxacurium chloride membrane leading to membrane disintegration. However, during the last two decades it has become apparent that some AMPs may also act by other mechanisms without destruction of the cell membrane, namely, acting on intracellular targets leading to inhibition of enzymatic activities, cell wall synthesis and RNA, DNA and protein synthesis [5, 17, 18]. The inhibition of RNA, DNA and protein synthesis in bacteria is often the result of AMPs interacting with DNA [19, 20]. Additionally, interaction with DNA by the hexapeptide WRWYCR and its D-enantiomers was shown to interfere with DNA repair [21]. DNA repair damage elicits the SOS response that is a conserved pathway essential for DNA repair and restart of stalled or collapsed replication forks, regulated by the repressor LexA and the activator RecA [22, 23]. In this study, we set out to investigate the mode of action (MOA) of LP5 using the pathogenic bacterium S. aureus.