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Structure of UDP‐N‐acetylglucosamine acyltransferase with a bound antibacterial pentadecapeptide

UDP‐N‐acetylglucosamine (UDP‐GlcNAc) acyltransferase (LpxA) catalyzes the first step of lipid A biosynthesis, the transfer of an R‐3‐hydroxyacyl chain from acyl carrier protein (ACP) to the glucosamine 3‐OH group of UDP‐GlcNAc. LpxA is essential for survival of Gram‐Negative bacteria. The crystal structure of the Escherichia coli LpxA homotrimer, determined previously at 2.6Å in the absence of substrates or inhibitors, revealed that LpxA adopts an unusual, left‐handed parallel β‐helix fold. We now present the crystal structure of E. coli LpxA with a bound pentadecapeptide (peptide 920) at 1.8 Å resolution. Three peptides, each in β‐hairpin conformation, are bound per LpxA homotrimer. Each peptide is located at the interface of the two adjacent subunits and interacts with residues from both subunits, some of which are implicated in substrate binding by mutagenesis. In vitro assays show that peptide 920 is a potent inhibitor of E. coli LpxA (Ki = 50 nM). It is competitive with respect to acyl‐ACP but not UDP‐GlcNAc. The compact β‐turn structure of peptide 920 bound to LpxA may open new approaches to the design of LpxA selective antibiotics.