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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:
Pathogens
Antibiotic Resistance
Infectious Diseases
Health & Wellbeing
Biochemistry
Chemistry
Structural biology
Organic Chemistry
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)