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| 001 | 904334 | ||
| 005 | 20220103172051.0 | ||
| 024 | 7 | _ | |a 10.3390/antibiotics10050529 |2 doi |
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| 100 | 1 | _ | |a López-Pérez, Arancha |0 0000-0002-2279-0176 |b 0 |
| 245 | _ | _ | |a Discovery of Pyrrolidine-2,3-diones as Novel Inhibitors of P. aeruginosa PBP3 |
| 260 | _ | _ | |a Basel |c 2021 |b MDPI |
| 336 | 7 | _ | |a article |2 DRIVER |
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| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1640941443_31144 |2 PUB:(DE-HGF) |
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| 520 | _ | _ | |a The 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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| 700 | 1 | _ | |a Freischem, Stefan |0 P:(DE-Juel1)165365 |b 1 |
| 700 | 1 | _ | |a Grimm, Immanuel |0 P:(DE-HGF)0 |b 2 |
| 700 | 1 | _ | |a Weiergräber, Oliver |0 P:(DE-Juel1)131988 |b 3 |u fzj |
| 700 | 1 | _ | |a Dingley, Andrew |0 P:(DE-Juel1)145681 |b 4 |
| 700 | 1 | _ | |a López-Alberca, María |0 P:(DE-HGF)0 |b 5 |
| 700 | 1 | _ | |a Waldmann, Herbert |0 P:(DE-HGF)0 |b 6 |
| 700 | 1 | _ | |a Vollmer, Waldemar |0 P:(DE-HGF)0 |b 7 |
| 700 | 1 | _ | |a Kumar, Kamal |0 0000-0003-3593-8421 |b 8 |
| 700 | 1 | _ | |a Vuong, Cuong |0 0000-0001-6125-3245 |b 9 |e Corresponding author |
| 773 | _ | _ | |a 10.3390/antibiotics10050529 |g Vol. 10, no. 5, p. 529 - |0 PERI:(DE-600)2681345-2 |n 5 |p 529 - |t Antibiotics |v 10 |y 2021 |x 2079-6382 |
| 856 | 4 | _ | |u https://juser.fz-juelich.de/record/904334/files/antibiotics-10-00529.pdf |y OpenAccess |
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