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

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.

• Authors: Jürgen Brem, 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 Hinchliffe, Gareth 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
• Journal: Nature chemistry (Nat Chem) Vol. 14 Issue 1 Pg. 15-24 (01 2022) ISSN: 1755-4349 [Electronic] England
• PMID: 34903857 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• beta-Lactamase Inhibitors
• beta-Lactams

Topics

• Animals
• Gram-Negative Bacteria (drug effects)
• Humans
• Mice
• Microbial Sensitivity Tests
• Protein Binding
• Structure-Activity Relationship
• beta-Lactamase Inhibitors (chemistry, metabolism, pharmacology)
• beta-Lactams (metabolism)