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Structure-activity relationships for inhibitors of Pseudomonas aeruginosa exoenzyme S ADP-ribosyltransferase activity

Saleeb, Michael ; Sundin, Charlotta ; Aglar, Öznur ; Pinto, Ana Filipa ; Ebrahimi, Mahsa ; Forsberg, Åke ; Schüler, Herwig LU orcid and Elofsson, Mikael (2018) In European Journal of Medicinal Chemistry 143. p.568-576
Abstract

During infection, the Gram-negative opportunistic pathogen Pseudomonas aeruginosa employs its type III secretion system to translocate the toxin exoenzyme S (ExoS) into the eukaryotic host cell cytoplasm. ExoS is an essential in vivo virulence factor that enables P. aeruginosa to avoid phagocytosis and eventually kill the host cell. ExoS elicits its pathogenicity mainly via ADP-ribosyltransferase (ADPRT) activity. We recently identified a new class of ExoS ADPRT inhibitors with in vitro IC50 of around 20 μM in an enzymatic assay using a recombinant ExoS ADPRT domain. Herein, we report structure-activity relationships of this compound class by comparing a total of 51 compounds based on a thieno [2,3-d]pyrimidin-4(3H)-one and... (More)

During infection, the Gram-negative opportunistic pathogen Pseudomonas aeruginosa employs its type III secretion system to translocate the toxin exoenzyme S (ExoS) into the eukaryotic host cell cytoplasm. ExoS is an essential in vivo virulence factor that enables P. aeruginosa to avoid phagocytosis and eventually kill the host cell. ExoS elicits its pathogenicity mainly via ADP-ribosyltransferase (ADPRT) activity. We recently identified a new class of ExoS ADPRT inhibitors with in vitro IC50 of around 20 μM in an enzymatic assay using a recombinant ExoS ADPRT domain. Herein, we report structure-activity relationships of this compound class by comparing a total of 51 compounds based on a thieno [2,3-d]pyrimidin-4(3H)-one and 4-oxo-3,4-dihydroquinazoline scaffolds. Improved inhibitors with in vitro IC50 values of 6 μM were identified. Importantly, we demonstrated that the most potent inhibitors block ADPRT activity of native full-length ExoS secreted by viable P. aeruginosa with an IC50 value of 1.3 μM in an enzymatic assay. This compound class holds promise as starting point for development of novel antibacterial agents.

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author
; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
ADP Ribose Transferases/antagonists & inhibitors, Bacterial Toxins/antagonists & inhibitors, Dose-Response Relationship, Drug, Molecular Structure, Poly(ADP-ribose) Polymerase Inhibitors/chemical synthesis, Pseudomonas aeruginosa/enzymology, Pyrimidinones/chemical synthesis, Quinazolines/chemical synthesis, Structure-Activity Relationship
in
European Journal of Medicinal Chemistry
volume
143
pages
9 pages
publisher
Elsevier Masson SAS
external identifiers
  • scopus:85036503688
  • pmid:29207339
ISSN
0223-5234
DOI
10.1016/j.ejmech.2017.11.036
language
English
LU publication?
no
additional info
Copyright © 2017 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
id
2da85d58-771e-44d5-b25b-90b77ec84115
date added to LUP
2024-11-21 17:50:48
date last changed
2025-05-09 17:31:45
@article{2da85d58-771e-44d5-b25b-90b77ec84115,
  abstract     = {{<p>During infection, the Gram-negative opportunistic pathogen Pseudomonas aeruginosa employs its type III secretion system to translocate the toxin exoenzyme S (ExoS) into the eukaryotic host cell cytoplasm. ExoS is an essential in vivo virulence factor that enables P. aeruginosa to avoid phagocytosis and eventually kill the host cell. ExoS elicits its pathogenicity mainly via ADP-ribosyltransferase (ADPRT) activity. We recently identified a new class of ExoS ADPRT inhibitors with in vitro IC50 of around 20 μM in an enzymatic assay using a recombinant ExoS ADPRT domain. Herein, we report structure-activity relationships of this compound class by comparing a total of 51 compounds based on a thieno [2,3-d]pyrimidin-4(3H)-one and 4-oxo-3,4-dihydroquinazoline scaffolds. Improved inhibitors with in vitro IC50 values of 6 μM were identified. Importantly, we demonstrated that the most potent inhibitors block ADPRT activity of native full-length ExoS secreted by viable P. aeruginosa with an IC50 value of 1.3 μM in an enzymatic assay. This compound class holds promise as starting point for development of novel antibacterial agents.</p>}},
  author       = {{Saleeb, Michael and Sundin, Charlotta and Aglar, Öznur and Pinto, Ana Filipa and Ebrahimi, Mahsa and Forsberg, Åke and Schüler, Herwig and Elofsson, Mikael}},
  issn         = {{0223-5234}},
  keywords     = {{ADP Ribose Transferases/antagonists & inhibitors; Bacterial Toxins/antagonists & inhibitors; Dose-Response Relationship, Drug; Molecular Structure; Poly(ADP-ribose) Polymerase Inhibitors/chemical synthesis; Pseudomonas aeruginosa/enzymology; Pyrimidinones/chemical synthesis; Quinazolines/chemical synthesis; Structure-Activity Relationship}},
  language     = {{eng}},
  month        = {{01}},
  pages        = {{568--576}},
  publisher    = {{Elsevier Masson SAS}},
  series       = {{European Journal of Medicinal Chemistry}},
  title        = {{Structure-activity relationships for inhibitors of Pseudomonas aeruginosa exoenzyme S ADP-ribosyltransferase activity}},
  url          = {{http://dx.doi.org/10.1016/j.ejmech.2017.11.036}},
  doi          = {{10.1016/j.ejmech.2017.11.036}},
  volume       = {{143}},
  year         = {{2018}},
}