TY  - JOUR
AU  - López-Pérez, Arancha
AU  - Freischem, Stefan
AU  - Grimm, Immanuel
AU  - Weiergräber, Oliver
AU  - Dingley, Andrew
AU  - López-Alberca, María
AU  - Waldmann, Herbert
AU  - Vollmer, Waldemar
AU  - Kumar, Kamal
AU  - Vuong, Cuong
TI  - Discovery of Pyrrolidine-2,3-diones as Novel Inhibitors of P. aeruginosa PBP3
JO  - Antibiotics
VL  - 10
IS  - 5
SN  - 2079-6382
CY  - Basel
PB  - MDPI
M1  - FZJ-2021-05904
SP  - 529 -
PY  - 2021
AB  - 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
LB  - PUB:(DE-HGF)16
C6  - 34064358
UR  - <Go to ISI:>//WOS:000653463000001
DO  - DOI:10.3390/antibiotics10050529
UR  - https://juser.fz-juelich.de/record/904334
ER  -