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

The outer membrane of Gram-negative bacteria is a specialized asymmetric lipid bilayer that serves as the primary defense mechanism against environmental threats and antibiotics. The outer leaflet is predominantly composed of lipopolysaccharide (LPS), a complex glycolipid consisting of Lipid A, a core oligosaccharide, and an O-antigen, while the inner leaflet contains phospholipids (Raetz & Whitfield, 2002). LPS is essential for bacterial viability and acts as a potent endotoxin, triggering systemic inflammatory responses via the Toll-like receptor 4 (TLR4) complex in humans (Alexander & Rietschel, 2001). This target is clinically significant because it is the primary site of action for last-resort antibiotics like polymyxins. Polymyxins bind to the negatively charged phosphate groups of Lipid A and adjacent phospholipids, displacing stabilizing divalent cations and causing lethal membrane disruption (Poirel et al., 2017). Understanding this target is crucial for developing new antimicrobial strategies to combat multi-drug resistant Gram-negative pathogens (Zhanel et al., 2019).

Other names

LipopolysaccharideEndotoxinLipid AOuter membrane glycolipidsBacterial outer membrane

Cationic cyclic peptides, such as polymyxins, interact electrostatically with the negatively charged phosphate groups of the Lipid A component of LPS and adjacent phospholipids (Poirel et al., 2017). This interaction leads to the displacement of divalent cations (Mg2+ and Ca2+) that normally stabilize the outer membrane structure. The resulting destabilization increases membrane permeability, allowing the drug to penetrate the periplasm and disrupt the inner cytoplasmic membrane, leading to the leakage of intracellular contents and cell death (StatPearls, 2023).