Metal binding pharmacophore click-derived discovery of new broad-spectrum metallo-ß-lactamase inhibitors.
Eur J Med Chem
; 257: 115473, 2023 Sep 05.
Article
em En
| MEDLINE
| ID: mdl-37209449
ABSTRACT
The emergence of metallo-ß-lactamases (MBLs) confers resistance to nearly all the ß-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 IC50 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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores de beta-Lactamases
/
Farmacóforo
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2023
Tipo de documento:
Article
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