Bacterial outer membrane and lipopolysaccharide (LPS/OM)

The bacterial outer membrane (OM) is a specialized asymmetric lipid bilayer found in Gram-negative bacteria that serves as a formidable permeability barrier against antibiotics and environmental stressors (Silhavy et al., 2010). Its outer leaflet is predominantly composed of lipopolysaccharide (LPS), a complex glycolipid consisting of Lipid A, a core oligosaccharide, and an O-antigen (Raetz & Whitfield, 2002). LPS is a potent endotoxin that triggers the human innate immune response by binding to the TLR4/MD-2 receptor complex, which can lead to sepsis and septic shock in severe infections (Opal, 2010). As a therapeutic target, the OM and LPS are critical because their disruption increases bacterial susceptibility to other drugs and can lead to direct cell death. Traditional antibiotics like polymyxins act by binding to the Lipid A moiety of LPS, displacing stabilizing divalent cations and causing membrane destabilization (Velkov et al., 2013). Modern drug discovery efforts also target the LPS transport (Lpt) machinery, such as the LptD protein, to prevent the assembly of the outer membrane (Sperandeo et al., 2019). This target is particularly relevant for treating multidrug-resistant pathogens like Pseudomonas aeruginosa and Acinetobacter baumannii (Zhanel et al., 2013).

Other names

EndotoxinLipid AO-antigenGram-negative outer membraneLPSOuter membrane

Disruption of outer membrane integrity via displacement of divalent cations (e.g., Mg2+ and Ca2+); binding to the Lipid A component of LPS; inhibition of LPS transport proteins such as LptD; enhancement of membrane permeability to facilitate the entry of other antibiotics (Velkov et al., 2013; Sperandeo et al., 2019).