Influences of Vibrio cholerae Lipid A Types on LPS Bilayer Properties

Abstract

Lipopolysaccharides (LPS) present in the outer leaflet of Gram-negative bacterial outer membranes protect the bacteria from external threats and influence antibiotic permeability as well as immune system recognition. The structure of lipid A, the anchor of an LPS molecule to the outer membrane, can make direct influences on membrane properties. Particularly, in Vibrio cholerae, a Gram-negative bacterium responsible for cholera, a severe diarrheal disease, modifications of lipid A structures grant antibiotic resistance and are a primary factor that led to the current cholera pandemic. However, the difference in structural properties incurred by such modifications has not been fully explored. In this work, five symmetric bilayer systems comprised of distinct lipid A structures of Vibrio cholerae LPS with O1 O-antigen were modeled and simulated to explore influences of different lipid A types on membrane properties. All-atom molecular dynamics simulations reveal that membrane properties such as hydrophobic thickness, acyl chain order parameter, and area per lipid are largely impacted by lipid A modifications due to differences in composition and acyl chain distortions. The modified lipid A is also less negatively charged, which possibly reveals a resistance mechanism to cationic antimicrobial peptide evasion. These findings present a possible explanation for Vibrio cholerae's immune system evasion properties and establish the differences between the lipid A types, which should be of use for any future study of the Gram-negative bacteria.

Modeling the Protective Role of Bacterial Lipopolysaccharides against Membrane-Rupturing Peptides

“…In the presence of a physiological salt concentration, i.e., n 1 ≈ 100 mM, the screening length becomes κ −1 ≈ 10 Å. The following inequality then holds: ϵ w κd/ϵ l ≫ 1, where the dielectric constant of lipids ϵ l ≈ 2 and d ≈ 8 nm (a typical headgroup-headgroup distance for the OM 10 or LPS bilayers 27 ). Under this condition, the electric coupling between the two layers is insignificant.…”

“…In the presence of a physiological salt concentration, i.e., n 1 ≈ 100 mM, the screening length becomes κ –1 ≈ 10 Å. The following inequality then holds: ϵ w κd /ϵ l ≫ 1, where the dielectric constant of lipids ϵ l ≈ 2 and d ≈ 8 nm (a typical headgroup-headgroup distance for the OM or LPS bilayers). Under this condition, the electric coupling between the two layers is insignificant. − Also the effects of dielectric discontinuities on the LPS surface can be taken into account through the parameter , A natural consequence of this is that the interaction between two charges on the membrane surface is about twice as strong as in the bulk phase.…”

“…Compared to the recent experimental ,,, and computational progress , in this area and despite its potential benefit in combating drug-resistant Gram-negative bacteria, our theoretical understanding of how the permeability of the OM depends on LPS remains far behind. Earlier theoretical efforts were focused on describing the interaction of peptides with LPS Re, ,, i.e., the simplest form of LPS for bacterial survival .…”

“…Variations of our model will likely offer guiding principles for designing peptide antibiotics, which are active against these bacteria. This would necessitate more complete biophysical characterizations of LPS–peptide systems, possibly along the line of what was done in refs , , , and .…”

Antibiofilm property and multiple action of peptide PEW300 against Pseudomonas aeruginosa

“…In recent decades, antimicrobial peptides (AMPs) have been regarded as promising therapeutics against biofilm-forming pathogens due to their broad-spectrum antibacterial activity and inability to induce resistance (Cardoso et al, 2019;Di Somma et al, 2020;Hancock et al, 2021). Several studies on bacteria in the planktonic state have shown that AMPs adopt a unique membrane-targeting mechanism of action, unlike conventional antibiotics with specific targets, which disturb bacterial membranes mainly by interaction with negatively charged phospholipids and cause cell death (Chen et al, 2020;Li et al, 2020a;Luna et al, 2021). Significantly different from bacteria in the planktonic state, the control of biofilm-encapsulated bacteria is very difficult because of their extremely low permeability to antimicrobial agents (Gilbert et al, 2002;Hall and Mah, 2017).…”