Discovery of novel UDP-N-Acetylglucosamine Acyltransferase (LpxA) inhibitors with activity against Pseudomonas aeruginosa

M. Dominic Ryan, Alastair L. Parkes, David Corbett, Anthony P. Dickie, Michelle Southey, Ole A. Andersen, Daniel B. Stein, Olivier R. Barbeau, Angelo Sanzone, Pia Thommes, John Barker, Ricky Cain, Christel Compper, Magali Dejob, Alain Dorali, Donnya Etheridge, Sian Evans, Adele Faulkner, Elise Gadouleau, Timothy GormanDenes Haase, Maisie Holbrow-wilshaw, Thomas Krulle, Xianfu Li, Christopher Lumley, Barbara Mertins, Spencer Napier, Rajesh Odedra, Kostas Papadopoulos, Vasileios Roumpelakis, Kate Spear, Emily Trimby, Jennifer Williams, Michael Zahn, Anthony D. Keefe, Ying Zhang, Holly T. Soutter, Paolo A. Centrella, Matthew A. Clark, John W. Cuozzo, Christoph E. Dumelin, Boer Deng, Avery Hunt, Eric A. Sigel, Dawn M. Troast, Boudewijn L. M. Dejonge

Research output: Contribution to journalArticlepeer-review

Abstract

This study describes a novel series of UDP-N-acetylglucosamine acyltransferase (LpxA) inhibitors that was identified through affinity-mediated selection from a DNA-encoded compound library. The original hit was a selective inhibitor of Pseudomonas aeruginosa LpxA with no activity against Escherichia coli LpxA. The biochemical potency of the series was optimized through an X-ray crystallography-supported medicinal chemistry program, resulting in compounds with nanomolar activity against P. aeruginosa LpxA (best half-maximal inhibitory concentration (IC50) <5 nM) and cellular activity against P. aeruginosa (best minimal inhibitory concentration (MIC) of 4 μg/mL). Lack of activity against E. coli was maintained (IC50 > 20 μM and MIC > 128 μg/mL). The mode of action of analogues was confirmed through genetic analyses. As expected, compounds were active against multidrug-resistant isolates. Further optimization of pharmacokinetics is needed before efficacy studies in mouse infection models can be attempted. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa.
Original languageEnglish
Pages (from-to)14377-14425
Number of pages49
JournalJournal of Medicinal Chemistry
Volume64
Issue number19
Early online date27 Sep 2021
DOIs
Publication statusPublished - 14 Oct 2021

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