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Structure–activity ...
Structure–activity relationships for inhibitors of Pseudomonas aeruginosa exoenzyme S ADP-ribosyltransferase activity
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- Saleeb, Michael (author)
- Umeå universitet,Kemiska institutionen
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- Sundin, Charlotta (author)
- Umeå universitet,Kemiska institutionen
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- Aglar, Öznur (author)
- Umeå universitet,Kemiska institutionen
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Pinto, Ana Filipa (author)
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Ebrahimi, Mahsa (author)
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- Forsberg, Åke (author)
- Umeå universitet,Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet)
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- Schüler, Herwig (author)
- Karolinska Institutet
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- Elofsson, Mikael (author)
- Umeå universitet,Kemiska institutionen
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(creator_code:org_t)
- Elsevier, 2018
- 2018
- English.
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In: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 143, s. 568-576
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Abstract
Subject headings
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- 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.
Subject headings
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- 2-Aminobenzamide
- ADP-Ribosyltransferase
- Bacterial exotoxins
- ExoS
- Pseudomonas aeruginosa
- Quinazolines
- Type III secretion
Publication and Content Type
- ref (subject category)
- art (subject category)
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