1. Metal binding pharmacophore click-derived discovery of new broad-spectrum metallo-β-lactamase inhibitors.
- Author
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Yan YH, Ding HS, Zhu KR, Mu BS, Zheng Y, Huang MY, Zhou C, Li WF, Wang Z, Wu Y, and Li GB
- Subjects
- beta-Lactamases metabolism, Structure-Activity Relationship, Monobactams, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents chemistry, beta-Lactamase Inhibitors pharmacology, beta-Lactamase Inhibitors chemistry, Pharmacophore
- Abstract
The emergence of metallo-β-lactamases (MBLs) confers resistance to nearly all the β-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 μM to 0.64 μM 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)- Published
- 2023
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