Polymyxin B Loosens Lipopolysaccharide Bilayer but Stiffens Phospholipid Bilayer
Lei Fu1, Mingwei Wan1, Shan Zhang1
1Key Laboratory of Theoretical and Computational Photochemistry, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, China.
Abstract:
Multidrug-resistant Gram-negative bacteria have increased the prevalence of a variety of serious diseases in modern times. Polymyxins are used as the last-line therapeutic options for the treatment of infections. However, the mechanism of action of polymyxins remains in dispute. In this work, we used a coarse-grained molecular dynamics simulation to investigate the mechanism of the cationic antimicrobial peptide polymyxin B (PmB) interacting with both the inner and outer membrane models of bacteria. Our results show that the binding of PmB disturbs the outer membrane by displacing the counterions, decreasing the orientation order of the lipopolysaccharide tail, and creating more lipopolysaccharide packing defects. Upon binding onto the inner membrane, in contrast to the traditional killing mechanism that antimicrobial peptides usually use to induce holes in the membrane, PmBs do not permeabilize the inner membrane but stiffen it by filling up the lipid packing defect, increasing the lipid tail order and the membrane bending rigidity as well as restricting the lipid diffusion. PmBs also mediate intermembrane contact and adhesion. These joint effects suggest that PmBs deprive the biological activity of Gram-negative bacteria by sterilizing the cell.
Insights
Polymyxin B (PmB) disrupts bacterial outer membranes and stiffens inner membranes, inhibiting Gram-negative bacteria. This study reveals PmB
Area of Science:
- Microbiology
- Biophysics
- Computational Chemistry
Background:
- Multidrug-resistant Gram-negative bacteria pose a significant global health threat.
- Polymyxins are critical last-line antibiotics for treating resistant bacterial infections.
- The precise mechanism by which polymyxins exert their antimicrobial effects is not fully understood.
Purpose of the Study:
- To investigate the molecular mechanism of polymyxin B (PmB) interaction with bacterial membranes.
- To elucidate how PmB affects both the outer and inner membranes of Gram-negative bacteria.
Main Methods:
- Coarse-grained molecular dynamics simulations were employed.
- Simulations modeled the interaction of PmB with bacterial inner and outer membrane models.
Main Results:
- PmB binding disturbed the outer membrane by displacing counterions and increasing lipopolysaccharide (LPS) packing defects.
- PmB binding stiffened the inner membrane, increasing lipid tail order, bending rigidity, and restricting lipid diffusion, without permeabilization.
- PmB mediated intermembrane contact and adhesion.
Conclusions:
- Polymyxin B's mechanism involves disrupting the outer membrane and altering the biophysical properties of the inner membrane.
- These combined effects lead to the inhibition of biological activity in Gram-negative bacteria.
- The findings provide a detailed molecular understanding of polymyxin action against resistant bacteria.
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