Gram-negative bacterial lipopolysaccharide and outer membrane phospholipids (LPS/OMP)

Gram-negative bacterial lipopolysaccharide (LPS) and outer membrane phospholipids constitute the essential asymmetric lipid bilayer that protects Gram-negative bacteria from environmental threats, including antibiotics. LPS, often referred to as endotoxin, consists of a hydrophobic lipid A anchor, a core oligosaccharide, and an O-antigen polysaccharide chain. It is a potent stimulator of the innate immune system, primarily through the TLR4/MD-2 receptor complex, and is a central mediator in the pathogenesis of sepsis and septic shock. From a therapeutic perspective, the negatively charged nature of LPS and the associated phospholipids serves as a primary docking site for cationic lipopeptide antibiotics like polymyxins. These drugs disrupt the structural integrity of the membrane, leading to rapid bactericidal activity against multi-drug resistant pathogens such as Pseudomonas aeruginosa and Acinetobacter baumannii. However, targeting these components carries significant risks of nephrotoxicity and requires careful monitoring of systemic inflammatory responses triggered by the release of membrane fragments.

Other names

LipopolysaccharideEndotoxinLipid AGram-negative outer membraneBacterial outer membrane phospholipids

Drugs such as polymyxins bind to the negatively charged phosphate groups of the lipid A moiety of lipopolysaccharide (LPS) via electrostatic interactions, displacing stabilizing divalent cations (Mg2+ and Ca2+). This interaction disrupts the packing of the outer membrane phospholipids and LPS, leading to increased membrane permeability, leakage of cytoplasmic contents, and ultimately bacterial cell death.