Cationic Biocides Tend to Embed into the Inner Layer of the Model Outer Membrane Vesicles of Gram-negative Bacteria: Computational Insights

Abstract

The outer membrane vesicles (OMVs), produced by many pathogenic bacteria, play a significant role in bacterial pathogenesis. They promote bacterial resistance to antibiotics and act as natural protective barriers. The study of OMVs is essential both for understanding the general mechanisms of bacterial pathogenicity and for the development of the antibacterial drugs. In this paper, we created model vesicle that imitate the OMVs of Gram-negative bacteria using molecular modeling techniques. To investigate the interaction of the cationic antimicrobial compounds with the outer lipopolysaccharide (LPS) monolayer and the inner phospholipid monolayer of the OMV membrane, we performed molecular dynamics simulations by placing molecules of the cationic antiseptic octenidine on the outside or inside of model vesicles. The interaction of octenidine with the outer and inner monolayer was significantly different: octenidine interacted weakly with the outer LPS surface of the model OMV, but exhibited high affinity for the phospholipids of the inner monolayer. To study the translocation of cationic antimicrobial molecules within model OMV, we performed steered molecular dynamics simulations. For all three cationic biocide molecules, antiseptic octenidine, photosensitizer octakis(cholinyl)zinc phthalocyanine, and dye methylene blue, it turned out that, along with the LPS of the outer membrane of the OMV, the phosphates of lipid A molecules represent the final barrier to their penetration into the model OMV.