Phosphoethanolamine-modified lipid A (PEtn-lipid A) (PEtn-lipid A)

Phosphoethanolamine-modified lipid A is a critical structural variant of the lipid anchor of lipopolysaccharide (LPS) found in the outer membrane of Gram-negative bacteria. This modification is primarily mediated by phosphoethanolamine transferases, such as the plasmid-encoded MCR (mobile colistin resistance) enzymes or chromosomally encoded EptA (Liu et al., 2016, Lancet Infect Dis). The addition of a phosphoethanolamine (PEtn) group to the 1 or 4' phosphate positions of lipid A reduces the overall negative charge of the bacterial cell surface (Gao et al., 2016, Nat Commun). This charge neutralization prevents the binding of cationic antimicrobial peptides (CAMPs) and polymyxin antibiotics, such as colistin and polymyxin B, which rely on electrostatic interactions to disrupt the membrane (Poirel et al., 2017, Clin Microbiol Rev). As a result, these modified lipids are a major determinant of high-level resistance to last-resort antibiotics in pathogens like Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. Targeting the enzymes responsible for this modification or developing drugs that bypass this charge-shielding mechanism are active areas of antimicrobial research.

Other names

Phosphoethanolamine-modified lipopolysaccharidepEtn-lipid ApEtn-LPSMCR-modified lipid APhosphoethanolamine-modified bacterial outer membrane

Polymyxins bind to the negatively charged phosphate groups of lipid A; phosphoethanolamine modification reduces this negative charge, preventing drug binding and subsequent membrane disruption (Baron et al., 2016, J Antimicrob Chemother).