UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) (LpxC)

UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a zinc-dependent metalloamidase that catalyzes the first committed step in the biosynthesis of lipopolysaccharide (LPS) in Gram-negative bacteria [1, 10]. Specifically, it performs the deacetylation of the LpxA product within the Raetz pathway to form lipid A, which serves as the essential hydrophobic anchor of the bacterial outer membrane [3, 16]. Because LPS is critical for maintaining the structural integrity and permeability barrier of the bacterial cell wall, LpxC has emerged as a high-priority target for the development of novel antibiotics against multidrug-resistant pathogens [14, 15]. Inhibition of this enzyme prevents the production of mature LPS, leading to increased membrane permeability and rapid bactericidal effects [7, 8]. Since LpxC is highly conserved across various Gram-negative species and lacks any known human homologs, it offers a high degree of therapeutic selectivity [2, 9]. However, clinical progression of LpxC inhibitors has been complicated by safety concerns such as cardiovascular toxicity and injection site inflammation [6, 13]. Overall, targeting the production of LPS remains a vital strategy for addressing severe Gram-negative infections and the associated risk of systemic sepsis [17, 19].

Other names

LPS productionLipopolysaccharide biosynthesisLipid A biosynthesisRaetz pathwayUDP-3-O-acyl-N-acetylglucosamine deacetylaseGram-negative bacterial cell wall synthesis

Competitive inhibition of the LpxC enzyme to arrest the lipid A biosynthesis pathway, thereby halting the production of lipopolysaccharide and compromising the integrity of the bacterial outer membrane [3, 8, 15].