Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors

Jürgen Brem (Lead / Corresponding author), Tharindi Panduwawala, Jon Ulf Hansen, Joanne Hewitt, Edgars Liepins, Pawel Donets, Laura Espina, Alistair J. M. Farley, Kirill Shubin, Gonzalo Gomez Campillos, Paula Kiuru, Shifali Shishodia, Daniel Krahn, Robert K. Leśniak, Juliane Schmidt (Adrian), Karina Calvopiña, María-Carmen Turrientes, Madeline E. Kavanagh, Dmitrijs Lubriks, Philip HinchliffeGareth W. Langley, Ali F. Aboklaish, Anders Eneroth, Maria Backlund, Andrei G. Baran, Elisabet I. Nielsen, Michael Speake, Janis Kuka, John Robinson, Solveiga Grinberga, Lindsay Robinson, Michael A. McDonough, Anna M. Rydzik, Thomas M. Leissing, Juan Carlos Jimenez-Castellanos, Matthew B. Avison, Solange Da Silva Pinto, Andrew D. Pannifer, Marina Martjuga, Emma Widlake, Martins Priede, Iva Hopkins Navratilova, Marek Gniadkowski, Anna Karin Belfrage, Peter Brandt, Jari Yli-Kauhaluoma, Eric Bacque, Malcolm G. P. Page, Fredrik Björkling, Jonathan M. Tyrrell, James Spencer, Pauline A. Lang, Pawel Baranczewski, Rafael Cantón, Stuart P. McElroy, Philip S. Jones, Fernando Baquero, Edgars Suna, Angus Morrison, Timothy R Walsh, Christopher J. Schofield (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-β-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential β-lactamase stable β-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.

Original languageEnglish
Pages (from-to)15-24
Number of pages10
JournalNature Chemistry
Volume14
Early online date13 Dec 2021
DOIs
Publication statusPublished - Jan 2022

Keywords

  • Drug discovery and development
  • Lead optimization
  • Medicinal chemistry

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