Polymyxins are increasingly used as the last-line therapeutic option for the treatment of infections caused by multidrug-resistant Gram-negative bacteria. Their primary bactericidal mechanism is attributed to their ability to impair membrane lipid organization and fluidity. However, another finding that seems contradictory is that polymyxins increase the rigidity of the bacterial membrane. This work used coarse-grained molecular dynamics (MD) simulations to investigate how Polymyxin B (PmB) affects the properties of an asymmetric Gram-negative bacterial outer membrane (OM) model and a symmetric phospholipid inner membrane (IM) model across various peptide concentrations, and compared PmB with an α-helical antimicrobial peptide Temporin L (TL). By analyzing the bending module of the membranes, peptide insertion depths, lipid packing defects, and lipid tail orientations, we found that PmBs primarily bind to the hydrophilic groups of lipopolysaccharide in the OM, resulting in molecule crowding within the headgroup region, which in turn effectively shielding the hydrophobic tails of lipopolysaccharide from exposure to the solvent. Collectively, these structural alterations contribute to an overall enhancement of OM rigidity. Nonetheless, PmBs slightly decrease the stiffness of IM by altering the orientation of phospholipids. In contrast, traditional AMPs like TL disrupt the integrity of both OM and IM. These mechanisms suggest that PmB may affect bacterial growth, cell division, and metabolism to achieve bactericidal effects, rather than through violent disruption of the membrane structure.
Chen et al. (Thu,) studied this question.