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- Title
Membrane charge and lipid packing determine polymyxin-induced membrane damage.
- Authors
Khondker, Adree; Dhaliwal, Alexander K.; Saem, Sokunthearath; Mahmood, Ahmad; Fradin, Cécile; Moran-Mirabal, Jose; Rheinstädter, Maikel C.
- Abstract
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. Adree Khondker et al. identify new mechanisms by which the membrane surface and lipid packing in the bacterial membrane control the penetration of antibiotics such as of polymyxin B. These findings indicate that biophysical factors might influence the resistance strength of bacteria to antibiotics.
- Subjects
POLYMYXIN; X-ray diffraction; THERAPEUTICS; ELECTROCHEMISTRY; GRAM-negative bacteria
- Publication
Communications Biology, 2019, Vol 2, Issue 1, pN.PAG
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-019-0297-6