Structural basis of the UDP-diacylglucosamine pyrophosphohydrolase LpxH inhibition by sulfonyl piperazine antibiotics

• DOI: 10.1073/pnas.1912876117
• Publication Date: 2020-02-11T01:25:59Z
• Authors: Jae Cho; Minhee Lee; C. Skyler Cochrane; Caroline G. Webster; Benjamin A. Fenton; Jinshi Zhao; Jiyong Hong; Pei Zhou
• Keywords: Piperazine; Sulfonyl

The UDP-2,3-diacylglucosamine pyrophosphate hydrolase LpxH is an essential lipid A biosynthetic enzyme that conserved in the majority of gram-negative bacteria. It has emerged as attractive novel antibiotic target due to recent discovery LpxH-targeting sulfonyl piperazine compound (referred AZ1) by AstraZeneca. However, molecular details AZ1 inhibition have remained unresolved, stymieing further development this class antibiotics. Here we report crystal structure Klebsiella pneumoniae complex with AZ1. We show fits snugly into L-shaped acyl chain-binding chamber its indoline ring situating adjacent active site, group adopting a sharp kink, and N-CF3-phenyl substituted reaching out far side chamber. Intriguingly, despite observation single conformation structure, our solution NMR investigation revealed presence second ligand invisible crystalline state. Together, these distinct conformations delineate cryptic inhibitor envelope expands observed footprint LpxH-bound enables design analogs enhanced potency enzymatic assays. These designed compounds display striking improvement activity over against wild-type K. pneumoniae, coadministration outer membrane permeability enhancers profoundly sensitizes Escherichia coli inhibitors. Remarkably, none occupies site LpxH, foretelling straightforward path for rapid optimization