Gram-negative bacterial outer membrane lipopolysaccharide (LPS) and associated phospholipid bilayer (LPS/OM)

The Gram-negative bacterial outer membrane is a specialized asymmetric lipid bilayer that serves as the primary interface between the bacterium and its environment. Its outer leaflet is predominantly composed of lipopolysaccharide (LPS), a complex glycolipid consisting of a conserved Lipid A anchor, a core oligosaccharide, and a variable O-antigen (Raetz & Whitfield, 2002). This structure functions as a highly selective permeability barrier, effectively excluding many hydrophobic antibiotics and detergents that would otherwise damage the cell (Nikaido, 2003). LPS is also a potent pathogen-associated molecular pattern (PAMP) recognized by the host immune system via Toll-like receptor 4 (TLR4), and its systemic release can lead to life-threatening sepsis and septic shock (Opal, 2010). Therapeutic agents like polymyxins target this structure by binding to the negatively charged phosphate groups of Lipid A, displacing stabilizing divalent cations and causing membrane disruption (Velkov et al., 2013). Newer developmental drugs, such as murepavadin, target the LptD protein responsible for transporting LPS to the outer membrane, thereby compromising the integrity of the bacterial envelope (Srinivas et al., 2010).

Other names

LipopolysaccharideEndotoxinBacterial outer membraneLipid A-core-O-antigen complexGram-negative cell envelope

Polymyxins bind to the Lipid A portion of LPS, displacing divalent cations (Mg2+ and Ca2+) that stabilize the membrane, leading to increased permeability and cell death (Velkov et al., 2013). Other agents inhibit the Lpt pathway, specifically the LptD/E complex, preventing the transport of LPS to the outer leaflet (Srinivas et al., 2010).