Open AccessMembrane charge and lipid packing determine polymyxin-induced membrane damage
Author(s) -
Adree Khondker,
Alexander Dhaliwal,
Sokunthearath Saem,
Ahmad Mahmood,
Cécile Fradin,
Jose M. MoranMirabal,
Maikel C. Rheinstädter
Publication year - 2019
Publication title -
communications biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.812
H-Index - 26
ISSN - 2399-3642
DOI - 10.1038/s42003-019-0297-6
Subject(s) - membrane , penetration (warfare) , biophysics , bacterial outer membrane , lipid bilayer , chemistry , materials science , surface charge , transmembrane protein , membrane potential , molecular dynamics , biochemistry , biology , computational chemistry , receptor , escherichia coli , operations research , gene , engineering
With the advent of polymyxin B (PmB) resistance in bacteria, the mechanisms for mcr -1 resistance are of crucial importance in the design of novel therapeutics. The mcr -1 phenotype is known to decrease membrane charge and increase membrane packing by modification of the bacterial outer membrane. We used X-ray diffraction, Molecular Dynamics simulations, electrochemistry, and leakage assays to determine the location of PmB in different membranes and assess membrane damage. By varying membrane charge and lipid tail packing independently, we show that increasing membrane surface charge promotes penetration of PmB and membrane damage, whereas increasing lipid packing decreases penetration and damage. The penetration of the PmB molecules is well described by a phenomenological model that relates an attractive electrostatic and a repulsive force opposing insertion due to increased membrane packing. The model applies well to several gram-negative bacterial strains and may be used to predict resistance strength.