UDP-3-O-(R-3-hydroxyacyl)GlcN N-acyltransferase (LpxD) catalyzes the essential amide bond forming acylation reaction between acylated UDP-glucosamine and acyl-ACP, in the third step of Lipid A biosynthesis in Gram-negative bacteria. In this study, a phage-bound random peptide library was screened to identify peptides that bind to E. coli LpxD in order to find in vivo active inhibitors of the acyltransferase. Of the twenty peptides identified after several rounds of bio-panning, three displayed antibacterial activity when expressed as thioredoxin fusions in E. coli, one of which (RJPXD33) represented 15% of the hits. RJPXD33 binds to E. coli LpxD with a Kd of 6 �M and is competitive with R-3-hydroxymyristoyl-ACP binding. The identification of inhibitory LpxD-binding peptides validates LpxD as an antibacterial target. RJPXD33 also binds to and inhibits E. coli UDP-GlcNAc acyltransferase (LpxA) with a Kd of 20 �M, unearthing the possibility for the development of dual-binding LpxA/LpxD inhibitors as novel antimicrobials.

Dual inhibition of early acyltransferases in <i>Eschericia coli</i> lipid A biosynthesis

244th National Meeting (2012)

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Dual inhibition of early acyltransferases in Eschericia coli lipid A biosynthesis