2. Academic Validation
  3. Discovery of Novel UDP- N-Acetylglucosamine Acyltransferase (LpxA) Inhibitors with Activity against Pseudomonas aeruginosa

Discovery of Novel UDP- N-Acetylglucosamine Acyltransferase (LpxA) Inhibitors with Activity against Pseudomonas aeruginosa

  • J Med Chem. 2021 Oct 14;64(19):14377-14425. doi: 10.1021/acs.jmedchem.1c00888.
M Dominic Ryan 1,  Alastair L Parkes 2,  David Corbett 3,  Anthony P Dickie 2,  Michelle Southey 2,  Ole A Andersen 2,  Daniel B Stein 4,  Olivier R Barbeau 2,  Angelo Sanzone 2,  Pia Thommes 3,  John Barker 2,  Ricky Cain 2,  Christel Compper 2,  Magali Dejob 2,  Alain Dorali 3,  Donnya Etheridge 2,  Sian Evans 2,  Adele Faulkner 2,  Elise Gadouleau 2,  Timothy Gorman 2,  Denes Haase 4,  Maisie Holbrow-Wilshaw 2,  Thomas Krulle 2,  Xianfu Li 2,  Christopher Lumley 2,  Barbara Mertins 2,  Spencer Napier 2,  Rajesh Odedra 3,  Kostas Papadopoulos 2,  Vasileios Roumpelakis 2,  Kate Spear 2,  Emily Trimby 3,  Jennifer Williams 3,  Michael Zahn 2,  Anthony D Keefe 5,  Ying Zhang 5,  Holly T Soutter 5,  Paolo A Centrella 5,  Matthew A Clark 5,  John W Cuozzo 5,  Christoph E Dumelin 5,  Boer Deng 5,  Avery Hunt 5,  Eric A Sigel 5,  Dawn M Troast 5,  Boudewijn L M DeJonge 1
Affiliations

Affiliations

  • 1 X-Biotix Therapeutics, 465 Waverly Oaks Road, Waltham, Massachusetts 02452, United States.
  • 2 Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • 3 Evotec UK, Anti-infectives, Block 23F, Alderley Park, Cheshire SK10 4TG, U.K.
  • 4 Evotec SE, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany.
  • 5 X-Chem, 100 Beaver Street, Waltham, Massachusetts 02453, United States.
PMID: 34569791 DOI: 10.1021/acs.jmedchem.1c00888
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.

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