Membrane charge and lipid packing determine polymyxin-induced membrane damage

Area of Science:

• Microbiology
• Biophysics
• Drug Discovery

Background:

• Polymyxin B (PmB) resistance is a growing threat, driven by mechanisms like mcr-1.
• The mcr-1 phenotype alters bacterial outer membranes by decreasing charge and increasing lipid packing.
• Understanding these alterations is crucial for developing new therapeutics against resistant bacteria.

Purpose of the Study:

• To investigate the mechanisms of polymyxin B (PmB) interaction with bacterial membranes.
• To determine how changes in membrane charge and lipid packing affect PmB penetration and membrane damage.
• To develop a predictive model for PmB resistance strength.

Main Methods:

• X-ray diffraction
• Molecular Dynamics (MD) simulations
• Electrochemistry
• Leakage assays

Main Results:

• Increasing bacterial membrane surface charge promotes PmB penetration and membrane damage.
• Increasing lipid tail packing in the membrane decreases PmB penetration and damage.
• A phenomenological model accurately describes PmB penetration, considering electrostatic attraction and repulsive forces from lipid packing.

Conclusions:

• Membrane charge and lipid packing are key factors influencing PmB efficacy.
• The developed model can predict PmB resistance strength in gram-negative bacteria.
• These findings provide a basis for designing novel therapeutics to overcome PmB resistance.