Gram-negative bacterial outer membrane lipopolysaccharide and cytoplasmic membrane

The Gram-negative bacterial cell envelope is a sophisticated multi-layered structure comprising an outer membrane (OM) and an inner cytoplasmic membrane (CM) (Source: Nature Reviews Microbiology, 2015). The OM is uniquely characterized by the presence of lipopolysaccharide (LPS), a glycolipid that serves as a potent endotoxin and a formidable permeability barrier against hydrophobic molecules and many antibiotics (Source: NIH, 2022). LPS is composed of three distinct regions: Lipid A, which anchors the molecule to the membrane; a core oligosaccharide; and an O-antigen polysaccharide chain. The cytoplasmic membrane is a phospholipid bilayer essential for maintaining the cell's electrochemical gradient, energy production, and selective transport of solutes. Therapeutic agents like polymyxins target this system by initially binding to the negatively charged phosphate groups of LPS, displacing stabilizing divalent cations (Mg2+ and Ca2+) and destabilizing the OM (Source: StatPearls, 2023). This allows the drug to penetrate the periplasm and insert into the CM, where it forms pores or disrupts the bilayer integrity, causing the leakage of vital intracellular contents and rapid cell death (Source: PubMed, 2019). While highly effective against multidrug-resistant pathogens, drugs targeting these membranes often face challenges due to potential toxicity in human cells and the emergence of resistance mechanisms such as LPS modification.

Other names

Gram-negative cell envelopeLPS and inner membraneBacterial outer and inner membranesEndotoxin and cytoplasmic membrane

Disruption of the outer membrane through competitive displacement of divalent cations from lipopolysaccharide (LPS), followed by insertion into and permeabilization of the cytoplasmic membrane, leading to loss of membrane potential and leakage of intracellular contents.