Discovery of novel UDP-N-acetylglucosamine acyltransferase (LpxA) inhibitors with activity against pseudomonas aeruginosa

DOI: 10.1021/acs.jmedchem.1c00888

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

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: September 2021
Diamond Proposal Number(s): 20021 , 23279

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.

Journal Keywords: Rodent models; Inhibitors; Amides; Peptides and proteins; Bacteria

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 29/09/2021 08:22

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Antibiotic Resistance Drug Discovery Infectious Diseases Pathogens Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)