Discovery of Pyrrolidine-2,3-diones as Novel Inhibitors of <em>P. aeruginosa</em> PBP3

• Main Authors: Arancha López-Pérez (Author), Stefan Freischem (Author), Immanuel Grimm (Author), Oliver Weiergräber (Author), Andrew J. Dingley (Author), María Pascual López-Alberca (Author), Herbert Waldmann (Author), Waldemar Vollmer (Author), Kamal Kumar (Author), Cuong Vuong (Author)
• Format: Book
• Published: MDPI AG, 2021-05-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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 <i>Pseudomonas aeruginosa</i>, 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 <i>P. aeruginosa</i> 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 <i>N</i>-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 <i>P. aeruginosa</i>.

Item Description

10.3390/antibiotics10050529
2079-6382