Gram-negative outer membrane lipopolysaccharide (LPS)

Gram-negative outer membrane lipopolysaccharide (LPS), commonly referred to as endotoxin, is a fundamental glycolipid that constitutes the majority of the outer leaflet of the Gram-negative bacterial outer membrane (Raetz & Whitfield, 2002). It is composed of three structural domains: the membrane-anchored Lipid A, a core oligosaccharide, and the O-antigen polysaccharide (Whitfield & Trent, 2014). LPS is vital for bacterial survival, acting as a robust physical barrier against antibiotics and environmental stressors, while also serving as a primary Pathogen-Associated Molecular Pattern (PAMP) recognized by the host's Toll-like receptor 4 (TLR4) (Park & Lee, 2013). During infection, the release of LPS into the bloodstream can trigger an overwhelming inflammatory response, leading to sepsis and septic shock (Steimle et al., 2016). Therapeutic interventions target LPS through various modalities, including the use of polymyxins (e.g., Colistin) which bind to Lipid A to disrupt membrane integrity, and newer classes of drugs like Zosurabalpin that inhibit the LptB2FGC transport complex responsible for moving LPS to the outer membrane (Zampaloni et al., 2024).

Other names

EndotoxinLipoglycanLipid A-core-O-antigen complexBacterial lipopolysaccharide

The primary mechanisms of action for drugs targeting lipopolysaccharide (LPS) involve the direct binding to the Lipid A moiety to disrupt the bacterial outer membrane (e.g., polymyxins), the inhibition of the Lpt protein machinery (e.g., LptD or LptB2FGC) to prevent LPS transport to the cell surface, or the neutralization of LPS-induced inflammatory signaling by antagonizing the TLR4/MD-2 receptor complex (Poirel et al., 2017; Zampaloni et al., 2024; Park & Lee, 2013).