UDP-3-O-(3-hydroxymyristoyl)glucosamine N-acyltransferase (LpxD) (LpxD)

UDP-3-O-(3-hydroxymyristoyl)glucosamine N-acyltransferase, commonly known as LpxD, is an essential enzyme in the biosynthesis of Lipid A, the hydrophobic anchor of lipopolysaccharide (LPS) in Gram-negative bacteria [1, 7]. It catalyzes the third step of the pathway, specifically the N-acylation of UDP-3-O-(3-hydroxymyristoyl)glucosamine using 3-hydroxymyristoyl-acyl carrier protein (ACP) as the acyl donor [7, 8]. Because Lipid A is vital for the structural integrity and barrier function of the bacterial outer membrane, LpxD is a critical target for the development of novel antibacterial agents [2, 4]. Inhibition of this enzyme leads to a reduction in LPS production, resulting in compromised membrane stability and bacterial cell death [3]. While no LpxD inhibitors have reached clinical use, research has identified several small molecules and peptide leads, such as RJPXD33, which demonstrate potent on-target activity [1, 2]. The conservation of LpxD across diverse Gram-negative pathogens makes it a promising candidate for broad-spectrum antibiotic discovery, particularly against multidrug-resistant strains [3, 4].

Other names

UDP-3-O-(3-hydroxyacyl)glucosamine N-acyltransferaseFirARifampicin resistance proteinUDP-3-O-(3-OHC14)-GlcN N-acyltransferaseUDP-3-O-(3-hydroxytetradecanoyl)glucosamine N-acyltransferase

Inhibition of LpxD enzymatic activity by competing with the acyl-ACP substrate or binding to the 4'-phosphopantetheine binding site, thereby disrupting Lipid A and lipopolysaccharide biosynthesis [1, 2].