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000904334 1001_ $$00000-0002-2279-0176$$aLópez-Pérez, Arancha$$b0
000904334 245__ $$aDiscovery of Pyrrolidine-2,3-diones as Novel Inhibitors of P. aeruginosa PBP3
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000904334 520__ $$aThe alarming threat of the spread of multidrug resistant bacteria currently leaves clinicians with very limited options to combat infections, especially those from Gram-negative bacteria. Hence, innovative strategies to deliver the next generation of antibacterials are urgently needed. Penicillin binding proteins (PBPs) are proven targets inhibited by β-lactam antibiotics. To discover novel, non-β-lactam inhibitors against PBP3 of Pseudomonas aeruginosa, we optimised a fluorescence assay based on a well-known thioester artificial substrate and performed a target screening using a focused protease-targeted library of 2455 compounds, which led to the identification of pyrrolidine-2,3-dione as a potential scaffold to inhibit the PBP3 target. Further chemical optimisation using a one-pot three-component reaction protocol delivered compounds with excellent target inhibition, initial antibacterial activities against P. aeruginosa and no apparent cytotoxicity. Our investigation revealed the key structural features; for instance, 3-hydroxyl group (R2) and a heteroaryl group (R1) appended to the N-pyrroldine-2,3-dione via methylene linker required for target inhibition. Overall, the discovery of the pyrrolidine-2,3-dione class of inhibitors of PBP3 brings opportunities to target multidrug-resistant bacterial strains and calls for further optimisation to improve antibacterial activity against P. aeruginosa
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000904334 7001_ $$0P:(DE-Juel1)165365$$aFreischem, Stefan$$b1
000904334 7001_ $$0P:(DE-HGF)0$$aGrimm, Immanuel$$b2
000904334 7001_ $$0P:(DE-Juel1)131988$$aWeiergräber, Oliver$$b3$$ufzj
000904334 7001_ $$0P:(DE-Juel1)145681$$aDingley, Andrew$$b4
000904334 7001_ $$0P:(DE-HGF)0$$aLópez-Alberca, María$$b5
000904334 7001_ $$0P:(DE-HGF)0$$aWaldmann, Herbert$$b6
000904334 7001_ $$0P:(DE-HGF)0$$aVollmer, Waldemar$$b7
000904334 7001_ $$00000-0003-3593-8421$$aKumar, Kamal$$b8
000904334 7001_ $$00000-0001-6125-3245$$aVuong, Cuong$$b9$$eCorresponding author
000904334 773__ $$0PERI:(DE-600)2681345-2$$a10.3390/antibiotics10050529$$gVol. 10, no. 5, p. 529 -$$n5$$p529 -$$tAntibiotics$$v10$$x2079-6382$$y2021
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