Anionic Lipid Clustering-Mediated Bactericidal Activity and Selective Toxicity of Quaternary Ammonium-Substituted Polycationic Pullulan against the Staphylococcus aureus Bacterial Membrane

Abstract

Non-amphiphilic polycations have recently been recognized to hold excellent antimicrobial potential with great mammalian cell compatibility. In a recent study, the excellent broad-spectrum bactericidal efficacy of a quaternary ammonium-substituted cationic pullulan (CP4) was demonstrated. Their selective toxicity and nominal probability to induce the acquisition of resistance among pathogens fulfill the fundamental requirements of new-generation antibacterials. However, there have been exiguous attempts in the literature to understand the antimicrobial activity of polycations against Gram-positive bacterial membranes. Here, for the first time, we have scrutinized the molecular level interactions of CP4 tetramers with a model Staphylococcus aureus membrane to understand their probable antibacterial function using molecular dynamics simulations. Our analysis reveals that the hydrophilic CP4 molecules are spontaneously adsorbed onto the membrane outer leaflet surface by virtue of strong electrostatic interactions and do not penetrate into the lipid tail hydrophobic region. This surface binding of CP4 is strengthened by the formation of anionic lipid-rich domains in their vicinity, causing lateral compositional heterogeneity. The major outcomes of the asymmetric accumulation of bulky polycationic CP4 on one leaflet are (i) anionic lipid segregation at the interaction site and (ii) a decrease in the cationic lipid acyl tail ordering and ease of water translocation across the lipid hydrophobic barrier. The membrane–CP4 interactions are strongly monitored by the ionic strength; a higher salt concentration weakens the binding of CP4 on the membrane surface. In addition, our study also substantiates the non-interacting behavior of CP4 oligomers with biomimetic 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membrane, indicating their cell selectivity and specificity against pathogenic membranes.

MoS2 nanosheet induced destructive alterations in the Escherichia coli bacterial membrane

“…Computational approaches such as MD simulations have been successfully employed to delineate the microscopic interaction details of a vast range of materials such as novel solvents, polymers and nanomaterials with the biological membranes. [34][35][36][37][38][39] The molecular-level picture of the interactions can help understand the probable macroscopic impact of external stimulants on biological domains as an alternative to tedious experiments in a cost-effective way. The present study outlines that the nanosheets can spontaneously penetrate inside the membrane hydrophobic core acting like ''nano-knives'' similar to the graphene sheets.…”

Wrapping–Trapping versus Extraction Mechanism of Bactericidal Activity of MoS2 Nanosheets against Staphylococcus aureus Bacterial Membrane

“…All the studied systems were comprised of a fully hydrated preequilibrated S. aureus bacterial membrane and MoS 2 nanosheets of different sizes. The pre-equilibrated S. aureus membrane configuration containing 250 lipids was retrieved from our earlier study 45 and was further utilized for preparing the membrane−MoS 2 systems. The S. aureus bacterial membrane considered was composed of three types of lipid headgroups (57% phosphatidylglycerol (PG), 38% lysylphosphatidylglycerol (Lys-PG), and 5% cardiolipin) attached with anteiso-branched myristoyl tails (a15:0).…”

“…All the studied systems were comprised of a fully hydrated pre-equilibrated S. aureus bacterial membrane and MoS 2 nanosheets of different sizes. The pre-equilibrated S. aureus membrane configuration containing 250 lipids was retrieved from our earlier study and was further utilized for preparing the membrane–MoS 2 systems. The S. aureus bacterial membrane considered was composed of three types of lipid headgroups (57% phosphatidylglycerol (PG), 38% lysyl-phosphatidylglycerol (Lys-PG), and 5% cardiolipin) attached with anteiso-branched myristoyl tails (a15:0). , These lipid molecules are thus named 1,2-dianteiso-myristoyl- sn -glycero-3-phosphoglycerol (AMPG), lysyl-1,2-dianteiso-myristoyl- sn -glycero-3-phosphoglycerol (LPG), and tetra-anteiso-myristoyl cardiolipin (ACL) and possess −1|e|, +1|e|, and −2|e| charges, respectively.…”

“…All of the simulations have been carried out using NAMD . The force-field employed for lipid molecules is in accordance with CHARMM36 lipid force-field , as parametrized earlier . The MoS 2 nanosheet parameters compatible with the CHARMM force-field were used as provided by Heinz and co-workers .…”

“…50 The force-field employed for lipid molecules is in accordance with CHARMM36 lipid force-field 51,52 as parametrized earlier. 45 The MoS 2 nanosheet parameters compatible with the CHARMM force-field were used as provided by Heinz and co-workers. 53 Water molecules were considered as the TIP3P model.…”