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

Gram-negative bacterial lipopolysaccharide (LPS) is a fundamental structural component of the outer membrane of Gram-negative bacteria, providing a robust permeability barrier against antibiotics and environmental stressors [Raetz & Whitfield, 2002, Annual Review of Biochemistry]. It is composed of three distinct regions: the hydrophobic Lipid A, a core oligosaccharide, and the distal O-antigen polysaccharide [StatPearls, "Gram-Negative Bacteria"]. Lipid A serves as the primary endotoxic moiety, recognized by the human TLR4/MD-2 receptor complex to trigger a potent inflammatory response, which can lead to sepsis and septic shock in severe infections [UniProt, "Lipopolysaccharide-binding protein"]. Therapeutic agents such as polymyxins (e.g., Polymyxin B and Colistin) target LPS by binding to the negatively charged phosphate groups of Lipid A, displacing stabilizing divalent cations like magnesium and calcium [PubMed, "Polymyxins: Antibacterial Activity, Pharmacokinetics, and Pharmacodynamics"]. This interaction disrupts the integrity of the outer membrane and its associated phospholipids, increasing permeability and ultimately resulting in bacterial cell death [Nature Reviews Microbiology, "The outer membrane of Gram-negative bacteria"]. Despite their efficacy, drugs targeting LPS are often associated with significant side effects, including nephrotoxicity and neurotoxicity, and the emergence of resistance through Lipid A modification is a growing clinical concern [PubMed, "Mechanism of polymyxin resistance"].

Other names

EndotoxinLipid AO-antigenBacterial outer membrane glycolipid

Binding to the Lipid A moiety of LPS, displacement of divalent cations (Mg2+ and Ca2+), disruption of the outer membrane integrity, and induction of cell lysis.