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

Saleeb, Michael (author)
Umeå universitet,Kemiska institutionen
Sundin, Charlotta (author)
Umeå universitet,Kemiska institutionen
Aglar, Öznur (author)
Umeå universitet,Kemiska institutionen
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Pinto, Ana Filipa (author)
Ebrahimi, Mahsa (author)
Forsberg, Åke (author)
Umeå universitet,Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet)
Schüler, Herwig (author)
Karolinska Institutet
Elofsson, Mikael (author)
Umeå universitet,Kemiska institutionen
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 (creator_code:org_t)
Elsevier, 2018
2018
English.
In: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 143, s. 568-576
  • Journal article (peer-reviewed)
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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