The Antimicrobial Peptide Polymyxin B1 Encounters Many Molecular Obstacles in the Periplasm En Route to the Inner Membrane of E. Coli

Abstract

Polymyxin B1 is an antibiotic that causes lysis of Gram-negative bacteria by disruption of the inner membrane. While the membrane action of antimicrobials is well-studied, how these antimicrobials negotiate the periplasmic space to arrive at the inner membrane is almost completely unexplored. To address this, we have employed molecular dynamics simulations to study the path taken by PMB1 through various atomistic models of the E.coli periplasm, containing a range of different proteins and the cell wall. Our models of the periplasm are perhaps the most complex in terms of system composition reported to date. The simulations reveal that PMB1 forms interactions with proteins that are free in solution as well as lipoproteins anchored to the outer membrane. Furthermore, the lipid moiety of PMB1 is shown to enter the hydrophobic cavities of LolA and LolB. Together the results show that PMB1 has a winding, obstacle-ridden path to the inner membrane. It is likely that this observation is true of other antibiotics that rely on diffusion rather than transporters to get across the periplasm.