The Power of Asymmetry: Architecture and Assembly of the Gram-Negative Outer Membrane Lipid Bilayer

Abstract

Determining the chemical composition of biological materials is paramount to the study of natural phenomena. Here, we describe the composition of model gram-negative outer membranes, focusing on the predominant assembly, an asymmetrical bilayer of lipid molecules. We also give an overview of lipid biosynthetic pathways and molecular mechanisms that organize this material into the outer membrane bilayer. An emphasis is placed on the potential of these pathways as targets for antibiotic development. We discuss deviations in composition, through bacterial cell surface remodeling, and alternative modalities to the asymmetric lipid bilayer. Outer membrane lipid alterations of current microbiological interest, such as lipid structures found in commensal bacteria, are emphasized. Additionally, outer membrane components could potentially be engineered to develop vaccine platforms. Observations related to composition and assembly of gram-negative outer membranes will continue to generate novel discoveries, broaden biotechnologies, and reveal profound mysteries to compel future research.

The Mla pathway is critical for Pseudomonas aeruginosa resistance to outer membrane permeabilization and host innate immune clearance

“…Gram-negative bacteria such as P. aeruginosa are protected by their outer membrane (OM), which is highly impermeable to toxic compounds such as detergents, bile salts, and antibiotics [5]. This OM is composed of an asymmetric bilayer containing lipopolysaccharide (LPS) on the outer leaflet and phospholipids (PLs) on the inner leaflet.…”

The phospholipid-repair system LplT/Aas in Gram-negative bacteria protects the bacterial membrane envelope from host phospholipase A2 attack

“…OM lipid asymmetry as an essential protective strategy of Gram-negative bacteria is believed to be facilitated by multiple mechanisms including the cytoplasmic Mla system, which promotes retrograde transport of diacyl PLs from OM to IM (41). The OM conformation is also mediated by the processes of membrane biogenesis including those for LPS, which also occur in the IM (19,30). Whether accumulation of LPL as a result of LplT/Aas inactivation alters the conformation and function of these biogenetic systems involved in the envelope homeostasis is unknown.…”

“…sPLA 2 , especially Group IIA, can penetrate through the cell wall of Grampositive bacteria to directly bind to the membrane, resulting in the high susceptibility of many Grampositive species (3). In contrast, Gram-negative bacteria exhibit much greater intrinsic resistance to sPLA 2 , which has been attributed to the unique structure of their additional outer envelope layer, the outer membrane (OM) (3,19). The OM of Gram-negative bacteria is arranged with an asymmetric lipid distribution: phospholipids (mainly phosphatidylethanolamine, PE) comprise the inner leaflet of the membrane, while the outer leaflet contains the complex glycolipid lipopolysaccharide (LPS).…”

The Lipid A from Rhodopseudomonas palustris Strain BisA53 LPS Possesses a Unique Structure and Low Immunostimulant Properties

“…Bacterial adaptation to environmental and metabolic needs typically results in modification of the membrane lipids, including LPS lipid A, mainly with regard to the fatty acid composition, to counterbalance the alterations effected by physical and chemical stress factors. Interestingly, lipid A is also involved in interaction with host receptors in both mammals and plants . Indeed, in mammals, lipid A is the LPS portion specifically recognized by the innate immunity receptor complex built up of Toll‐like receptor 4 (TLR4) and myeloid differentiation protein‐2 (MD‐2) .…”

“…An excessive stimulation by agonistic LPS on the TLR4/MD‐2 complex results in septic shock that could lead to organ failure, whereas moderate stimulation leads to the establishment of an inflammatory response representing a non‐specific resistance to the invading microorganism . On the other hand, some lipid A structures render the LPS an antagonist agent by preventing the binding of toxic LPS to the receptor complex, thus inhibiting or limiting the dangerous damage on infected cells . Consequently, the investigation of lipid A molecules from non‐human pathogen bacteria is extremely important to identify novel lipid As displaying inhibitory activity towards the production of pro‐inflammatory cytokines in mammals upon stimulation by toxic lipid A molecules.…”