Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 32, Pages E7587-E7594Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1803975115
Keywords
outer membrane; polymyxin; neutron reflectometry; lipopolysaccharide; phase transition
Categories
Funding
- ISIS beam time Awards [1600025, 1510379, 1400031]
- STFC
- Newcastle University
- OJ-Bio Ltd.
Ask authors/readers for more resources
The outer membrane (OM) of Gram-negative bacteria is a robust, impermeable, asymmetric bilayer of outer lipopolysaccharides (LPSs) and inner phospholipids containing selective pore proteins which confer on it the properties of a molecular sieve. This structure severely limits the variety of antibiotic molecules effective against Gram-negative pathogens and, as antibiotic resistance has increased, so has the need to solve the OM permeability problem. Polymyxin B (PmB) represents those rare antibiotics which act directly on the OM and which offer a distinct starting point for new antibiotic development. Here we investigate PmB's interactions with in vitro OM models and show how the physical state of the lipid matrix of the OM is a critical factor in regulating the interaction with the antimicrobial peptide. Using neutron reflectometry and infrared spectroscopy, we reveal the structural and chemical changes induced by PmB on OM models of increasing complexity. In particular, only a tightly packed model reproduced the temperature-controlled disruption of the asymmetric lipid bilayer by PmB observed in vivo. By measuring the order of outer-leaflet LPS and inner-leaflet phospholipids, we show that PmB insertion is dependent on the phase transition of LPS from the gel to the liquid crystalline state. The demonstration of a lipid phase transition in the physiological temperature range also supports the hypothesis that bacteria grown at different temperatures adapt their LPS structures to maintain a homeoviscous OM.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available