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

UDP-3-O-(3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a zinc-dependent metalloenzyme essential for the biosynthesis of Lipid A, the hydrophobic anchor of lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria (UniProt, 2024; NIH, 2023). It catalyzes the second reaction of the Raetz pathway, which serves as the first committed and rate-limiting step in Lipid A production, making it a critical control point for bacterial viability and structural integrity (Science Translational Medicine, 2023). Because Lipid A is indispensable for nearly all Gram-negative pathogens and the enzyme has no mammalian homologue, LpxC is a high-priority target for developing novel antibiotics against multidrug-resistant (MDR) strains such as Pseudomonas aeruginosa and Klebsiella pneumoniae (Frontiers in Microbiology, 2025). Small-molecule inhibitors like ACHN-975 and the clinical candidate LPC-233 target the enzyme's active site, coordinating with the essential zinc ion to block catalysis and cause rapid bactericidal effects (PubMed, 2019). While these inhibitors show potent activity in preclinical models, their clinical development has been historically challenged by dose-limiting cardiovascular toxicities, specifically hypotension, which remains a key hurdle in therapeutic optimization (BioWorld, 2023; mBio, 2014).

Other names

UDP-3-O-acyl-N-acetylglucosamine deacetylaseUDP-3-O-acyl-GlcNAc deacetylaseUDP-3-O-((3R)-3-hydroxymyristoyl)-N-acetylglucosamine amidohydrolaseLpxC deacetylaseLpxC enzyme

Competitive inhibition of the LpxC enzyme active site, which prevents the deacetylation of UDP-3-O-(3-hydroxymyristoyl)-GlcNAc. This blockages halts the biosynthesis of Lipid A, the essential hydrophobic anchor of lipopolysaccharides, leading to compromised outer membrane integrity and rapid bacterial cell death.