Interactions between polymyxin B and various bacterial membrane mimics: A molecular dynamics study

Polymyxin B (PMB) is clinically used as a last-line therapy against life-threatening Gram-negative "superbugs". However, thorough understanding of the membrane actions of PMB at a molecular level is still lacking. In this work, a variety of bacterial membrane mimics with varying lipid compositions were built, and their interactions with PMB were systematically investigated using coarse-grained molecular dynamics simulation. PMB demonstrated characteristic preference to specific lipid species during its interaction with different membrane systems, such as the rough mutant lipipolysacchrides (Re LPS) preference in an outer membrane (OM) or the cardiolipin and POPG affinity in an inner membrane (IM). As a result of the lipid-specific actions, complicated membrane interaction states of PMB were observed, including adsorption on the OM surface. In contrast, for the IM or a mutative OM containing "impurity lipids" like POPE, POPG or lipid A, it could insert into the membrane via its acyl chain. Such actions of PMB influence the structure and lipid mobility of the membrane. In particular, the OM-bound PMB breaks the synchronous movement of Re LPS molecules in the outer leaflet and makes them diffuse more randomly, while its insertion into IM blocks the phospholipid diffusion and makes the membrane more homogeneous in the trajectory space. Our results provide insight into the action mechanism of PMB at a membrane level and a foundation for developing novel and safer polymyxin strategies for better clinical use.