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Publication Abstract from PubMed

The emergence of metallo-beta-lactamases (MBLs) confers resistance to nearly all the beta-lactam antibiotics, including carbapenems. Currently, there is a lack of clinically useful MBL inhibitors, making it crucial to discover new inhibitor chemotypes that can potently target multiple clinically relevant MBLs. Herein we report a strategy that utilizes a metal binding pharmacophore (MBP) click approach to identify new broad-spectrum MBL inhibitors. Our initial investigation identified several MBPs including phthalic acid, phenylboronic acid and benzyl phosphoric acid, which were subjected to structural transformations using azide-alkyne click reactions. Subsequent structure-activity relationship analyses led to the identification of several potent broad-spectrum MBL inhibitors, including 73 that manifested IC(50) values ranging from 0.00012 muM to 0.64 muM against multiple MBLs. Co-crystallographic studies demonstrated the importance of MBPs in engaging with the MBL active site anchor pharmacophore features, and revealed the unusual two-molecule binding modes with IMP-1, highlighting the critical role of flexible active site loops in recognizing structurally diverse substrates/inhibitors. Our work provides new chemotypes for MBL inhibition and establishes a MBP click-derived paradigm for inhibitor discovery targeting MBLs as well as other metalloenzymes.

Metal binding pharmacophore click-derived discovery of new broad-spectrum metallo-beta-lactamase inhibitors.,Yan YH, Ding HS, Zhu KR, Mu BS, Zheng Y, Huang MY, Zhou C, Li WF, Wang Z, Wu Y, Li GB Eur J Med Chem. 2023 May 13;257:115473. doi: 10.1016/j.ejmech.2023.115473. PMID:37209449^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.