Molecular mechanism of action of imidazolium carbosilane dendrimers on the outer bacterial membrane – from membrane damage to permeability to antimicrobial endolysin
Description
The interaction of cationic imidazolium CBS dendrimers with three different bacterial membrane models (E. coli, P. aeruginosa, and A. baumannii) was determined. The results suggest that the mechanism of action strictly depends on the types of dendrimers, the charge distribution of groups capable of establishing interactions with membranes, and the lipid composition (Fig. 9). Dendrimer D1 with methylimidazolium groups, to which cationic moieties are more exposed, tends to aggregate, leading to a destructive interaction with the model membrane. The lipid bilayer is disrupted due to the increased concentration of D1 dendrimers on the membrane. Dendrimer D2, with pyridineimidazolium groups, does not destroy liposomes. Its mechanism of action is based on an affinity to the membrane and its penetration, which leads to changes in membrane fluidity and permeability. D2 dendrimer permeabilizes the membrane without completely destroying it, allowing the antimicrobial protein (endolysin) to be transported through the lipid membrane and reach the peptidoglycan. Thermodynamic analysis shows an increase in the affinity of D2 dendrimers to liposomes when the concentration of negatively charged lipids in the membrane increases (the reaction changes from endothermic to exothermic). This suggests that a high concentration of CL and DOPG in the membrane guarantees a higher affinity of antimicrobial dendrimers. The higher the composition of CL or DOPG, the greater disruption and changes in membrane permeability and fluidity are observed. This phenomenon allows us to use pyridineimidazolium D2 dendrimers not only as bacterial membrane disruptors but also as permeabilization agents for other antimicrobials, such as endolysin, to improve the antimicrobial effect without forming pores in the membrane. In this case, inactive concentrations of dendrimers, D2, together with endolysin, enhance the antimicrobial effect of this protein. The obtained results are very important for understanding the mechanism of action of antimicrobial agents against different strains of bacteria. They also clearly show that the mechanisms of action of positively charged systems are not the same for all Gram-negative bacteria. Knowledge of the relationship between the influence of lipid composition and the mechanism of action of dendrimers will allow the development of better antibacterial agents.
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Narodowe Centrum Nauki
No. 2021/43/D/NZ6/00560