Lipopolysaccharide (LPS), also known as endotoxin, forms the outer leaflet of the outer membrane of Gram-negative bacteria, where it functions as both a permeability barrier and a potent activator of the host immune system. It plays a central role in bacterial physiology and pathogenicity and represents a major structural and functional component of the cell envelope, alongside other bacterial cell wall constituents such as peptidoglycan. LPS is therefore of major interest in microbiology, immunology, and biomedical research.

Molecular Structure

LPS is composed of three covalently linked domains: lipid A, the core oligosaccharide, and the O-antigen polysaccharide. Lipid A constitutes the hydrophobic membrane anchor and is responsible for most of the endotoxic activity. It consists of a β-1,6-linked D-glucosamine disaccharide phosphorylated at the 1 and 4′ positions and acylated with six to seven fatty acid chains, typically C12–C16 hydroxylated chains such as β-hydroxymyristate, which confer amphipathic properties.

The core oligosaccharide is linked to lipid A via one to four residues of 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo) and contains a conserved inner region enriched in heptoses and phosphates, followed by a more variable outer region composed mainly of hexoses and additional substituents such as ethanolamine. The distal O-antigen consists of 20 to 100 repeating oligosaccharide units, with sequences that vary between bacterial strains, thereby determining serotype specificity.

Physicochemical and Biological Properties

LPS exhibits strong amphipathic behavior and readily forms micelles in aqueous solutions, with a critical micelle concentration in the range of approximately 1–10 ng/mL. It is thermally stable and highly resistant to proteolytic and lipolytic degradation. Structural heterogeneity is common and arises from phase-variable chemical modifications, such as the addition of phosphoethanolamine groups, which alter surface charge and modulate resistance to host defense mechanisms.

Based on the presence and length of the O-antigen, LPS molecules are classified into smooth (S-form, full-length O-antigen), rough (R-form, truncated or absent O-antigen with exposed core), and semi-rough (Sr-form) variants. These structural differences strongly influence bacterial virulence, serum resistance, and interactions with the host immune system.