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Structure-activity relationships for inhibitors of Pseudomonas aeruginosa exoenzyme S ADP-ribosyltransferase activity
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0003-2721-6074
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2018 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 143, p. 568-576Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2018. Vol. 143, p. 568-576
Keyword [en]
2-Aminobenzamide, ADP-Ribosyltransferase, Bacterial exotoxins, ExoS, Pseudomonas aeruginosa, Quinazolines, Type III secretion
National Category
Organic Chemistry Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-143429DOI: 10.1016/j.ejmech.2017.11.036PubMedID: 29207339OAI: oai:DiVA.org:umu-143429DiVA, id: diva2:1169324
Available from: 2017-12-23 Created: 2017-12-23 Last updated: 2018-01-13Bibliographically approved

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Saleeb, MichaelSundin, CharlottaForsberg, ÅkeElofsson, Mikael
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