On the antimicrobial activity of various peptide-based dendrimers of similar architecture

Abstract

Antimicrobial drug resistance is a major human health threat. Among the many attempts to tackle this problem, the synthesis of antimicrobial compounds that mimic natural antimicrobial peptides appears as a promising approach. Peptide-based dendrimers can be designed to have higher potency than natural antimicrobial peptides and at the same time they can evade the bacterial defense system. Novel dendrimers with similar chemical structure but varying potency in terms of minimum inhibitory concentration were designed. The dependency between dendrimer structure and antibacterial activity as well as their capacity to attack model cell membranes was studied. The data suggests that supramolecular structure in terms of charge distribution and amphiphilicity, rather than net charge, is the main driver for disruption of cellular membranes and this correlates well with dendrimer hemolytic activity.

Figure 1

Chemical structures of the studied dendrimers D100, D101 and D103.

Figure 2

Adsorption isotherms for peptide-based dendrimer D100 (green), D101 (red), and D103 (blue) on silica. ∆f (circles) and ∆d (crosses) are plotted as a function of bulk dendrimer concentration. Lines act as guides to the eye.

Figure 3

∆d plotted as a function of ∆f for 6 µM of D100 (green), D101 (red) and D103 (blue) interacting with a supported lipid bilayer of POPC. At ∆d, ∆f = 0, dendrimers were added to the supported lipid bilayer. A pure adsorption process (1) occurred for all three dendrimers (increase in ∆d and decrease in ∆f). For D101, the adsorption was followed by desorption (2) and layer rearrangement (3).

Figure 4

∆d plotted as a function of ∆f for D100 (green) and D103 (blue) interacting with a POPC bilayer at 6 (open symbols) and 15 µM (filled symbols) concentration. At ∆d, ∆f = 0, dendrimers were added to the supported lipid bilayer. Increase in ∆d and decrease in ∆f indicated adsorption of dendrimers to the SLB (1). For D100 at 15 µM, there was a second adsorption regime with increased dissipation pointing to softening of the layer (2).

Scheme 1

Synthesis route for dendrimer D100, D101 and D103.