Bacterial outer membrane lipopolysaccharide and phospholipids (LPS/PL)

The bacterial outer membrane (OM) of Gram-negative bacteria is a specialized asymmetric bilayer that serves as the first line of defense against environmental threats and antibiotics (Nature Reviews Microbiology, 2010). It is primarily composed of phospholipids in the inner leaflet and lipopolysaccharides (LPS) in the outer leaflet, which provide a robust permeability barrier (NCBI Bookshelf, 2023). LPS, often referred to as endotoxin, consists of three distinct regions: the hydrophobic Lipid A, a core oligosaccharide, and an O-antigen polysaccharide (StatPearls, 2023). This target is clinically significant because it is the site of action for last-resort antibiotics like polymyxins, which disrupt the membrane by binding to the anionic Lipid A component (PubMed, 2019). Beyond its structural role, LPS is a potent inducer of the innate immune response through the TLR4 receptor complex, making it a central player in the pathogenesis of sepsis and septic shock (Nature Reviews Immunology, 2013). Targeting the OM lipids or the transport machinery represents a key strategy for developing new treatments against multi-drug resistant Gram-negative pathogens (Journal of Biological Chemistry, 2017). Resistance to drugs targeting this structure often involves modifications to the Lipid A phosphate groups, which reduces the binding affinity of cationic antibiotics (Frontiers in Microbiology, 2020).

Other names

EndotoxinLipoglycanOuter membrane lipidsLipid AGram-negative outer membrane

Cationic antibiotics like polymyxins bind to the negatively charged phosphate groups of Lipid A and phospholipids, displacing stabilizing divalent cations (Ca2+ and Mg2+), which leads to increased membrane permeability, leakage of cytoplasmic contents, and cell death (StatPearls, 2023).