marcescens towards our chimeras as a combined treatment including the chelating agent EDTA resulted in a reduction in the number of viable cells

comparable to that seen for a more susceptible Gram-negative strain of E. coli treated similarly (not shown). This indicated that the innate differences in susceptibility between the two Gram-negative GSK2118436 concentration species could be completely eliminated after destabilization of the outer membrane. When designing new antimicrobial peptides it is generally accepted that a minimum length is required in order for the peptide BI-D1870 purchase to span or transverse the cell membrane. However, the majority of studies have focused on optimizing the length of AMPs assuming it to adopt a helical conformation [25, 26, 40]. By contrast, due to their design with alternating hydrophobic and cationic

residues our peptidomimetics are not expected to adopt an amphipathic helical active confirmation, but rather an extended conformation with some degree of secondary structure as indicated by analysis of their CD spectra [22, 23]. Recently, it has been shown that neither global amphipathicity nor regular secondary structure may be required for short peptides to effectively interact with bacterial membranes [19, 58], but the optimal length of such peptides has not been rationalized by mechanistic experiments. Only oligomers with a chain length above 12 residues, i.e. the 16-meric peptidomimetic 4c were able to cause such a substantial leakage of ATP that the number of viable cells were reduced (Figure 4C and 4D). We attribute this to the inability of chimeras 4a and 4b to produce a critical degree of membrane disruption thus leaving a sufficient level selleck compound of intracellular ATP for the cells to survive (Figure 4A and 4B for chimera 4a).

This is to our knowledge the first time that the effect of chain length has been investigated on the membrane-perturbing activity of peptidomimetics without a dominant secondary structure. Also, we believe that our study is the first that directly, in a kinetic fashion, correlate membrane permeabilization with actual killing kinetics. Previously, the interaction of α-peptide/β-peptides chimeras with liposomal model membranes and murine fibroblast was described [24]. Most recently, we investigated Resveratrol their cytotoxicity and haemolytic activity towards human HeLa cells and erythrocytes, respectively [23]. Besides confirming that members of this subclass of peptidomimetics exhibit a broad antimicrobial activity that includes resistant strains and food-borne pathogens, the purpose of the present study was to undertake a more detailed investigation of their mode of action. The present contribution describes their interaction with viable bacterial cells, and we found that these antimicrobial peptidomimetics have a mode of action involving the cell membrane. The observed membrane disruption depends strongly on chain length, and it may be impeded if the outer membrane in a Gram-negative bacterium possesses an innate altered composition.