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  3. Metal binding pharmacophore click-derived discovery of new broad-spectrum metallo-β-lactamase inhibitors

Metal binding pharmacophore click-derived discovery of new broad-spectrum metallo-β-lactamase inhibitors

  • Eur J Med Chem. 2023 Sep 5;257:115473. doi: 10.1016/j.ejmech.2023.115473.
Yu-Hang Yan 1,  Hao-Sheng Ding 1,  Kai-Rong Zhu 1,  Bin-Song Mu 1,  Yang Zheng 1,  Meng-Yi Huang 1,  Cong Zhou 1,  Wen-Fang Li 2,  Zhenling Wang 2,  Yong Wu 3,  Guo-Bo Li 4
Affiliations

Affiliations

  • 1 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
  • 2 State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 3 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
  • 4 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 37209449 DOI: 10.1016/j.ejmech.2023.115473
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 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.

Keywords

Antimicrobial resistance; Click chemistry; Metal binding pharmacophore; Metallo-β-lactamase; Metalloenzyme.

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