2. Academic Validation
  3. Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors

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

  • Nat Chem. 2022 Jan;14(1):15-24. doi: 10.1038/s41557-021-00831-x.
Jürgen Brem 1,  Tharindi Panduwawala 2,  Jon Ulf Hansen 3,  Joanne Hewitt 4,  Edgars Liepins 5,  Pawel Donets 5,  Laura Espina 6,  Alistair J M Farley 2,  Kirill Shubin 5,  Gonzalo Gomez Campillos 2,  Paula Kiuru 7,  Shifali Shishodia 2 8,  Daniel Krahn 2,  Robert K Leśniak 2,  Juliane Schmidt Adrian 2,  Karina Calvopiña 2,  María-Carmen Turrientes 9,  Madeline E Kavanagh 2 10,  Dmitrijs Lubriks 5,  Philip Hinchliffe 11,  Gareth W Langley 2 12,  Ali F Aboklaish 6,  Anders Eneroth 13,  Maria Backlund 13,  Andrei G Baran 5,  Elisabet I Nielsen 14,  Michael Speake 4 15,  Janis Kuka 5,  John Robinson 4 15,  Solveiga Grinberga 5,  Lindsay Robinson 4 15,  Michael A McDonough 2,  Anna M Rydzik 2 16,  Thomas M Leissing 2,  Juan Carlos Jimenez-Castellanos 11 17,  Matthew B Avison 11,  Solange Da Silva Pinto 2,  Andrew D Pannifer 4,  Marina Martjuga 5,  Emma Widlake 6,  Martins Priede 5,  Iva Hopkins Navratilova 4,  Marek Gniadkowski 18,  Anna Karin Belfrage 19,  Peter Brandt 19 20,  Jari Yli-Kauhaluoma 7,  Eric Bacque 21,  Malcolm G P Page 22,  Fredrik Björkling 23,  Jonathan M Tyrrell 6 11,  James Spencer 11,  Pauline A Lang 2,  Pawel Baranczewski 24,  Rafael Cantón 9,  Stuart P McElroy 4 15,  Philip S Jones 4 15,  Fernando Baquero 9,  Edgars Suna 5,  Angus Morrison 4 15,  Timothy R Walsh 6,  Christopher J Schofield 25
Affiliations

Affiliations

  • 1 Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK. [email protected].
  • 2 Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
  • 3 Statens Serum Institut, Copenhagen, Denmark.
  • 4 University of Dundee, European Screening Centre, BioCity Scotland, Newhouse, UK.
  • 5 Latvian Institute of Organic Synthesis, Riga, Latvia.
  • 6 Department of Medical Microbiology, Institute of infection & Immunity, Cardiff University, Cardiff, UK.
  • 7 Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
  • 8 Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.
  • 9 Department of Microbiology, Ramón y Cajal University Hospital and Ramón y Cajal Institute for Health Research (IRYCIS), Madrid, Spain.
  • 10 Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • 11 School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
  • 12 Charles River Laboratories, Saffron Walden, UK.
  • 13 Department of Pharmacy, Uppsala Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala University, Uppsala, Sweden.
  • 14 Department of Pharmacy, Uppsala University, Uppsala, Sweden.
  • 15 BioAscent Discovery Ltd, Newhouse, UK.
  • 16 Research and Early Development, Respiratory & Immunology, AstraZeneca, Mölndal, Sweden.
  • 17 Chemical Biology of Antibiotics, Centre for Infection & Immunity (CIIL), Pasteur Institute, INSERM U1019 - CNRS UMR 9017, Lille, France.
  • 18 Department of Molecular Microbiology, National Medicines Institute, Warsaw, Poland.
  • 19 Department of Medicinal Chemistry, Drug Design and Discovery, Uppsala University, Uppsala, Sweden.
  • 20 Beactica Therapeutics AB, Uppsala, Sweden.
  • 21 Evotec Infectious Diseases Lyon, Marcy l'Etoile, France.
  • 22 Jacobs University Bremen gGmbH, Bremen, Germany.
  • 23 Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
  • 24 Department of Pharmacy, SciLifeLab Drug Discovery and Development Platform, ADME of Therapeutics Facility, Uppsala University, Uppsala, Sweden.
  • 25 Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK. [email protected].
PMID: 34903857 DOI: 10.1038/s41557-021-00831-x
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.

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