Gram-negative bacterial outer membrane phospholipids and divalent cation cross-bridges

The outer membrane of Gram-negative bacteria acts as a formidable permeability barrier, protecting the cell from environmental stressors and many antibiotics (Nikaido, 2003). This structural integrity is largely maintained by the presence of divalent cations, specifically magnesium (Mg2+) and calcium (Ca2+), which form essential cross-bridges between negatively charged phosphate groups on lipopolysaccharides (LPS) and phospholipids (Clifton et al., 2015). These ionic interactions neutralize electrostatic repulsion between anionic lipid heads, effectively 'zipping' the membrane components together to create a dense, stable leaflet (Hancock, 1997). Disruption of these cation bridges is a primary mechanism for several classes of antibiotics, most notably the polymyxins, such as colistin and polymyxin B (Trimble et al., 2016). These cationic drugs possess a higher affinity for the lipid phosphate groups than the native divalent cations, allowing them to competitively displace the ions and destabilize the membrane (Moore et al., 1986). This displacement leads to increased membrane permeability, a phenomenon termed 'self-promoted uptake,' which facilitates the drug's entry and eventual disruption of the cytoplasmic membrane (Hancock, 1984). Targeting these cross-bridges is a critical strategy for treating multidrug-resistant infections caused by pathogens such as Pseudomonas aeruginosa and Acinetobacter baumannii (Trimble et al., 2016). However, therapeutic use is often limited by the potential for nephrotoxicity and the emergence of resistance mechanisms, such as the mcr-1 gene, which modifies the anionic target sites to reduce drug binding (Liu et al., 2016).

Other names

LPS-divalent cation bridgesOuter membrane cation-stabilized complexesMg2+/Ca2+ lipid cross-linksDivalent cation-phospholipid bridges

Competitive displacement of divalent cations (Mg2+, Ca2+) from phosphate groups of the outer membrane, leading to membrane disruption and self-promoted uptake.