Lipopolysaccharide and bacterial cell membranes (LPS) (LPS)

The bacterial cell envelope of Gram-negative bacteria is a complex, multi-layered structure consisting of an asymmetric outer membrane and an inner cytoplasmic membrane. The outer membrane is uniquely characterized by the presence of lipopolysaccharide (LPS), a glycolipid whose Lipid A moiety provides structural integrity and serves as a potent endotoxin (NCBI, 2023). This envelope acts as a formidable permeability barrier against many antibiotics, but it is specifically targeted by the polymyxin class of drugs, such as Colistin and Polymyxin B (StatPearls, 2024). These drugs interact electrostatically with the negatively charged phosphate groups of Lipid A, displacing stabilizing divalent cations like magnesium and calcium. This interaction leads to the disruption of the outer membrane and subsequent insertion into the cytoplasmic membrane, causing leakage of essential intracellular contents and cell death (PubMed, 2022). While highly effective against multi-drug resistant pathogens, targeting these membranes is associated with significant clinical challenges, including dose-limiting nephrotoxicity and the emergence of resistance through LPS modification (Nature Reviews Microbiology, 2019).

Other names

Lipid AEndotoxinGram-negative outer membraneBacterial cytoplasmic membraneInner membraneLPS

Polymyxins bind to the Lipid A component of lipopolysaccharide (LPS) in the outer membrane via electrostatic interactions, displacing divalent cations (Mg2+ and Ca2+). This increases outer membrane permeability, allowing the drug to penetrate and disrupt the cytoplasmic membrane, leading to cell lysis.