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Updated: Jun 23, 2026
Expression, Detergent Solubilization, and Purification of a Membrane Transporter, the MexB Multidrug Resistance Protein
Published on: December 3, 2010
Molecular Crowding Alters the Interactions of Polymyxin Lipopeptides within the Periplasm of E. coli: Insights from
Iain P S Smith1, Conrado Pedebos2,3, Syma Khalid3
1School of Chemistry, University of Southampton, Southampton SO17 1BJ, U.K.
Abstract:
The cell envelope of Gram-negative bacteria is a crowded tripartite architecture that separates the cell interior from the external environment. Two membranes encapsulate the aqueous periplasm, which contains the cell wall. Little is known about the mechanisms via which antimicrobial peptides move through the periplasm from the outer membrane to their site of action, the inner membrane. We utilize all-atom molecular dynamics to study two antimicrobial peptides, polymyxins B1 and E, within models of the E. coli periplasm crowded to different extents. In a simple chemical environment, both PMB1 and PME bind irreversibly to the cell wall. The presence of specific macromolecules leads to competition with the polymyxins for cell wall interaction sites, resulting in polymyxin dissociation from the cell wall. Chemical complexity also impacts interactions between polymyxins and Braun's lipoprotein; thus, the interaction modes of lipoprotein antibiotics within the periplasm are dependent upon the nature of the other species present.
Insights
Antimicrobial peptides like polymyxins can bind to the bacterial cell wall. However, other molecules in the periplasm can disrupt this binding, affecting how these drugs reach their target.
Area of Science:
- Microbiology
- Biophysics
- Computational Biology
Background:
- Gram-negative bacteria possess a complex cell envelope with an outer membrane, periplasm, and inner membrane.
- The periplasm's role in antimicrobial peptide (AMP) transport to the inner membrane is not well understood.
- Understanding AMP translocation is crucial for developing new antibacterial strategies.
Purpose of the Study:
- To investigate the translocation mechanisms of polymyxins B1 (PMB1) and E (PME) through the Gram-negative bacterial periplasm.
- To explore how periplasmic crowding and chemical complexity influence polymyxin-cell wall and polymyxin-lipoprotein interactions.
Main Methods:
- All-atom molecular dynamics simulations were employed.
- Models of the *E. coli* periplasm with varying degrees of macromolecular crowding were utilized.
- Interactions between polymyxins, cell wall components, and Braun's lipoprotein were analyzed.
Main Results:
- In a simplified environment, PMB1 and PME irreversibly bind to the cell wall.
- The presence of macromolecules in the periplasm leads to competition for cell wall binding sites, causing polymyxin dissociation.
- Periplasmic chemical complexity alters the interaction modes between polymyxins and Braun's lipoprotein.
Conclusions:
- Periplasmic crowding and chemical composition significantly impact polymyxin translocation and efficacy.
- The interaction of lipoprotein antibiotics within the periplasm is highly dependent on the surrounding molecular environment.
- These findings provide insights into the challenges of AMP delivery to the inner membrane of Gram-negative bacteria.
