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

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 IC 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 IC 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 IC value of 1.3 μM in an enzymatic assay. This compound class holds promise as starting point for development of novel antibacterial agents.

Synthesis and biological evaluation of dehydroabietic acid-pyrimidine hybrids as antitumor agents

“…The pyrimidine moiety, as one of the most important heterocyclic scaffolds, is considered a privileged structure in medicinal chemistry for drug discovery. 19,20 Pyrimidine derivatives have been reported to have a broad spectrum of biological activities, such as antiviral, 21,22 antibacterial, 23 antifungal, 24 anti-inammatory, 25,26 COX-2 inhibitors, 27 antituberculosis, 28 herbicidal 29 and insecticidal 30 activities. Moreover, previous studies have found that numerous pyrimidine derivatives exhibited promising anticancer activity.…”

Secretory System Components as Potential Prophylactic Targets for Bacterial Pathogens

“…An approved therapy relies on antibiotics. Indirect approaches, including virulence blockers, have not been available commercially despite excellent work by many groups [183][184][185][186][187][188][189][190][191].…”

Targeting ADP-ribosylation as an antimicrobial strategy

“…Further, additional strategies have instead exploited the antimicrobial protection provided by polyphenolic compounds from grape extract [295]; the screening of individual compounds has led to identify twelve molecules active against CTX, where four out of twelve acting through inhibition of ART activity. Similarly, molecules inhibiting ExoS ART activity with an IC 50 of 1.3 µM have been proposed as starting point for a precise targeting of virulence factors [296]. The high conservation of ADPr mechanisms throughout the evolution suggests that in-depth studies are needed in order to ensure that therapeutic molecules targeting bacterial toxins would not be specific for endogenous mechanisms of ADPr in the host, whose alteration may cause serious side effects.…”