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 Gorman; Denes 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

doi:10.1021/acs.jmedchem.1c00888

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 journal › Article › peer-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 language	English
Pages (from-to)	14377-14425
Number of pages	49
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	19
Early online date	27 Sept 2021
DOIs	https://doi.org/10.1021/acs.jmedchem.1c00888
Publication status	Published - 14 Oct 2021

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Ryan, M. D., Parkes, A. L., Corbett, D., Dickie, A. P., Southey, M., Andersen, O. A., Stein, D. B., Barbeau, O. R., Sanzone, A., Thommes, P., Barker, J., Cain, R., Compper, C., Dejob, M., Dorali, A., Etheridge, D., Evans, S., Faulkner, A., Gadouleau, E., ... Dejonge, B. L. M. (2021). Discovery of novel UDP-N-Acetylglucosamine Acyltransferase (LpxA) inhibitors with activity against Pseudomonas aeruginosa. Journal of Medicinal Chemistry, 64(19), 14377-14425. https://doi.org/10.1021/acs.jmedchem.1c00888

@article{1235ef99b9624f9d8217008243967209,

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

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.",

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

year = "2021",

month = oct,

day = "14",

doi = "10.1021/acs.jmedchem.1c00888",

language = "English",

volume = "64",

pages = "14377--14425",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "19",

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Ryan, MD, Parkes, AL, Corbett, D, Dickie, AP, Southey, M, Andersen, OA, Stein, DB, Barbeau, OR, Sanzone, A, Thommes, P, Barker, J, Cain, R, Compper, C, Dejob, M, Dorali, A, Etheridge, D, Evans, S, Faulkner, A, Gadouleau, E, Gorman, T, Haase, D, Holbrow-wilshaw, M, Krulle, T, Li, X, Lumley, C, Mertins, B, Napier, S, Odedra, R, Papadopoulos, K, Roumpelakis, V, Spear, K, Trimby, E, Williams, J, Zahn, M, Keefe, AD, Zhang, Y, Soutter, HT, Centrella, PA, Clark, MA, Cuozzo, JW, Dumelin, CE, Deng, B, Hunt, A, Sigel, EA, Troast, DM & Dejonge, BLM 2021, 'Discovery of novel UDP-N-Acetylglucosamine Acyltransferase (LpxA) inhibitors with activity against Pseudomonas aeruginosa', Journal of Medicinal Chemistry, vol. 64, no. 19, pp. 14377-14425. https://doi.org/10.1021/acs.jmedchem.1c00888

TY - JOUR

T1 - Discovery of novel UDP-N-Acetylglucosamine Acyltransferase (LpxA) inhibitors with activity against Pseudomonas aeruginosa

AU - Ryan, M. Dominic

AU - Parkes, Alastair L.

AU - Corbett, David

AU - Dickie, Anthony P.

AU - Southey, Michelle

AU - Andersen, Ole A.

AU - Stein, Daniel B.

AU - Barbeau, Olivier R.

AU - Sanzone, Angelo

AU - Thommes, Pia

AU - Barker, John

AU - Cain, Ricky

AU - Compper, Christel

AU - Dejob, Magali

AU - Dorali, Alain

AU - Etheridge, Donnya

AU - Evans, Sian

AU - Faulkner, Adele

AU - Gadouleau, Elise

AU - Gorman, Timothy

AU - Haase, Denes

AU - Holbrow-wilshaw, Maisie

AU - Krulle, Thomas

AU - Li, Xianfu

AU - Lumley, Christopher

AU - Mertins, Barbara

AU - Napier, Spencer

AU - Odedra, Rajesh

AU - Papadopoulos, Kostas

AU - Roumpelakis, Vasileios

AU - Spear, Kate

AU - Trimby, Emily

AU - Williams, Jennifer

AU - Zahn, Michael

AU - Keefe, Anthony D.

AU - Zhang, Ying

AU - Soutter, Holly T.

AU - Centrella, Paolo A.

AU - Clark, Matthew A.

AU - Cuozzo, John W.

AU - Dumelin, Christoph E.

AU - Deng, Boer

AU - Hunt, Avery

AU - Sigel, Eric A.

AU - Troast, Dawn M.

AU - Dejonge, Boudewijn L. M.

PY - 2021/10/14

Y1 - 2021/10/14

N2 - 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.

AB - 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.

U2 - 10.1021/acs.jmedchem.1c00888

DO - 10.1021/acs.jmedchem.1c00888

M3 - Article

SN - 0022-2623

VL - 64

SP - 14377

EP - 14425

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 19

ER -

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

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