ArticleNature chemistry2022
Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors.
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Article in Nature chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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35citing papers in PubMed
4.1field-weighted citation impact, top 4% of its field
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35 citing papers in PubMed, 78 citations in OpenAlex.
- Chelate-conjugated β-lactams resensitize metallo-β-lactamase IMP-1-producing gram-negative bacteria against carbapenem antibiotics.Microbiology spectrum · 2026Article
- Random Forest Modeling to Predict Small Molecule Accumulation in Gram-Negative Bacteria.ACS infectious diseases · 2026Article
- Zinc displacement and metabolic interference: cobalt ion-mediated therapy for broad-spectrum CRKP-resistant pneumonia via inhalable microspheres.Nature communications · 2026Article
- Development of Water-Trapping Pyrrole-2-carboxylic Acids as Broad-Spectrum Metallo-β-lactamase Inhibitors.Journal of medicinal chemistry · 2026Article
- Dipiperazine-Phenyl Derivatives Based on Convergent Molecular Platforms Can Reverse Multidrug Resistance in Gram-Negative Bacteria by Inhibiting Efflux and Permeabilizing Cell Membranes.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Light-Activated Metal-Dependent Protein Degradation: A Heterobifunctional Ruthenium(II) Photosensitizer Targeting New Delhi Metallo-β-lactamase 1.Journal of the American Chemical Society · 2025Article
- Navigating the complexities of drug development for metallo-β-lactamase inhibitors.RSC medicinal chemistry · 2025Review
- Harder than Metal: Challenging Antimicrobial Resistance with Metallo-β-lactamase Inhibitors.Journal of medicinal chemistry · 2025Review
- Fighting Antimicrobial Resistance: Innovative Drugs in Antibacterial Research.Angewandte Chemie (International ed. in English) · 2025Review
- Strategic re-engineering of antibiotics.Nature reviews bioengineering · 2025Article
- Elucidation of critical chemical moieties of metallo-β-lactamase inhibitors and prioritisation of target metallo-β-lactamases.Journal of enzyme inhibition and medicinal chemistry · 2024Review
- Mechanism-guided strategies for combating antibiotic resistance.World journal of microbiology & biotechnology · 2024Review
- New Delhi Metallo-Beta-Lactamase Inhibitors: A Systematic Scoping Review.Journal of clinical medicine · 2024Article
- The Triple Combination of Meropenem, Avibactam, and a Metallo-β-Lactamase Inhibitor Optimizes Antibacterial Coverage Against Different β-Lactamase Producers.Engineering (Beijing, China) · 2024Article
- Development of an inhibitor of the mutagenic SOS response that suppresses the evolution of quinolone antibiotic resistance.Chemical science · 2024Article
- Cell-active small molecule inhibitors validate the SNM1A DNA repair nuclease as a cancer target.Chemical science · 2024Article
- Rational Design of Benzobisheterocycle Metallo-β-Lactamase Inhibitors: A Tricyclic Scaffold Enhances Potency against Target Enzymes.Journal of medicinal chemistry · 2024Article
- Identification and characterization of CIM-1, a carbapenemase that adds to the family of resistance factors against last resort antibiotics.Communications biology · 2024Article
- The antibiotic crisis: On the search for novel antibiotics and resistance mechanisms.Microbial biotechnology · 2024Article
- Using permeation guidelines to design new antibiotics-A PASsagE into Pseudomonas aeruginosa.Clinical and translational medicine · 2024Article
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Authors and funding
61 authors at 15 institutions in 11 countries.
Jürgen BremDepartment of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK. jurgen.brem@chem.ox.ac.uk.ORCID http://orcid.org/0000-0002-0137-3226
Tharindi PanduwawalaDepartment of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0001-7095-1336
Jon Ulf HansenStatens Serum Institut, Copenhagen, Denmark.
Joanne HewittUniversity of Dundee, European Screening Centre, BioCity Scotland, Newhouse, UK.
Edgars LiepinsLatvian Institute of Organic Synthesis, Riga, Latvia.
Pawel DonetsLatvian Institute of Organic Synthesis, Riga, Latvia.ORCID http://orcid.org/0000-0003-4358-2429
Laura EspinaDepartment of Medical Microbiology, Institute of infection & Immunity, Cardiff University, Cardiff, UK.
Alistair J M FarleyDepartment of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
Kirill ShubinLatvian Institute of Organic Synthesis, Riga, Latvia.
Gonzalo Gomez CampillosDepartment of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0002-2405-8421
Paula KiuruDrug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.ORCID http://orcid.org/0000-0001-6084-684X
Shifali ShishodiaDepartment of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0001-8727-3877
Daniel KrahnDepartment of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
Robert K LeśniakDepartment of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
Juliane Schmidt AdrianDepartment of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
Karina CalvopiñaDepartment of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
María-Carmen TurrientesDepartment of Microbiology, Ramón y Cajal University Hospital and Ramón y Cajal Institute for Health Research (IRYCIS), Madrid, Spain.
Madeline E KavanaghDepartment of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0002-4735-1559
Dmitrijs LubriksLatvian Institute of Organic Synthesis, Riga, Latvia.ORCID http://orcid.org/0000-0002-8014-4172
Philip HinchliffeSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
Gareth W LangleyDepartment of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0003-0875-3712
Ali F AboklaishDepartment of Medical Microbiology, Institute of infection & Immunity, Cardiff University, Cardiff, UK.
Anders EnerothDepartment of Pharmacy, Uppsala Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala University, Uppsala, Sweden.
Maria BacklundDepartment of Pharmacy, Uppsala Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala University, Uppsala, Sweden.ORCID http://orcid.org/0000-0002-6253-816X
Andrei G BaranLatvian Institute of Organic Synthesis, Riga, Latvia.
Elisabet I NielsenDepartment of Pharmacy, Uppsala University, Uppsala, Sweden.ORCID http://orcid.org/0000-0003-0725-214X
Michael SpeakeUniversity of Dundee, European Screening Centre, BioCity Scotland, Newhouse, UK.
Janis KukaLatvian Institute of Organic Synthesis, Riga, Latvia.
John RobinsonUniversity of Dundee, European Screening Centre, BioCity Scotland, Newhouse, UK.
Solveiga GrinbergaLatvian Institute of Organic Synthesis, Riga, Latvia.
Lindsay RobinsonUniversity of Dundee, European Screening Centre, BioCity Scotland, Newhouse, UK.
Michael A McDonoughDepartment of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0003-4664-6942
Anna M RydzikDepartment of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
Thomas M LeissingDepartment of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
Juan Carlos Jimenez-CastellanosSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
Matthew B AvisonSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
Solange Da Silva PintoDepartment of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
Andrew D PanniferUniversity of Dundee, European Screening Centre, BioCity Scotland, Newhouse, UK.
Marina MartjugaLatvian Institute of Organic Synthesis, Riga, Latvia.
Emma WidlakeDepartment of Medical Microbiology, Institute of infection & Immunity, Cardiff University, Cardiff, UK.ORCID http://orcid.org/0000-0001-6721-8643
Martins PriedeLatvian Institute of Organic Synthesis, Riga, Latvia.ORCID http://orcid.org/0000-0002-9655-8345
Iva Hopkins NavratilovaUniversity of Dundee, European Screening Centre, BioCity Scotland, Newhouse, UK.
Marek GniadkowskiDepartment of Molecular Microbiology, National Medicines Institute, Warsaw, Poland.
Anna Karin BelfrageDepartment of Medicinal Chemistry, Drug Design and Discovery, Uppsala University, Uppsala, Sweden.ORCID http://orcid.org/0000-0002-6257-4064
Peter BrandtDepartment of Medicinal Chemistry, Drug Design and Discovery, Uppsala University, Uppsala, Sweden.ORCID http://orcid.org/0000-0002-2885-2016
Jari Yli-KauhaluomaDrug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.ORCID http://orcid.org/0000-0003-0370-7653
Eric BacqueEvotec Infectious Diseases Lyon, Marcy l'Etoile, France.
Malcolm G P PageJacobs University Bremen gGmbH, Bremen, Germany.ORCID http://orcid.org/0000-0002-0276-8174
Fredrik BjörklingDepartment of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.ORCID http://orcid.org/0000-0001-7018-8334
Jonathan M TyrrellDepartment of Medical Microbiology, Institute of infection & Immunity, Cardiff University, Cardiff, UK.
James SpencerSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.ORCID http://orcid.org/0000-0002-4602-0571
Pauline A LangDepartment of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0003-3187-1469
Pawel BaranczewskiDepartment of Pharmacy, SciLifeLab Drug Discovery and Development Platform, ADME of Therapeutics Facility, Uppsala University, Uppsala, Sweden.ORCID http://orcid.org/0000-0001-5772-6791
Rafael CantónDepartment of Microbiology, Ramón y Cajal University Hospital and Ramón y Cajal Institute for Health Research (IRYCIS), Madrid, Spain.ORCID http://orcid.org/0000-0003-1675-3173
Stuart P McElroyUniversity of Dundee, European Screening Centre, BioCity Scotland, Newhouse, UK.
Philip S JonesUniversity of Dundee, European Screening Centre, BioCity Scotland, Newhouse, UK.
Fernando BaqueroDepartment of Microbiology, Ramón y Cajal University Hospital and Ramón y Cajal Institute for Health Research (IRYCIS), Madrid, Spain.
Edgars SunaLatvian Institute of Organic Synthesis, Riga, Latvia.ORCID http://orcid.org/0000-0002-3078-0576
Angus MorrisonUniversity of Dundee, European Screening Centre, BioCity Scotland, Newhouse, UK.
Timothy R WalshDepartment of Medical Microbiology, Institute of infection & Immunity, Cardiff University, Cardiff, UK.
Christopher J SchofieldDepartment of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK. christopher.schofield@chem.ox.ac.uk.ORCID http://orcid.org/0000-0002-0290-6565
University of Oxford · GBLatvijas Organiskās Sintēzes Institūts · LVUniversity of Dundee · GBUppsala University · SECardiff University · GBUniversity of Bristol · GBInstituto Cajal · ESUniversity of Helsinki · FICentre National de la Recherche Scientifique · FRConstructor University · DEMedical College of Wisconsin · USNarodowy Instytut Leków · PLScripps Research Institute · USStatens Serum Institut · DKUniversity of Copenhagen · DK
Funding
A Mechanism-Based Approach to Metallo-beta-Lactamase InhibitionR01AI100560 · NIAID · CASE WESTERN RESERVE UNIVERSITY · PI BONOMO, ROBERT A., SPENCER, JAMES · 2012 to 2022
$4.4MBiotechnology and Biological Sciences Research Council BB/L01386X/1Biotechnology and Biological Sciences Research Council BB/M012107/1Biotechnology and Biological Sciences Research Council BB/S50676X/1Cancer Research UK 24759Cancer Research UK C9047/A24759Medical Research Council MR/P007295/1Medical Research Council MR/S013768/1Medical Research Council MR/S013768/2NIAID NIH HHS R01 AI100560Wellcome Trust 099141/Z/12/ZWellcome Trust 106244/Z/14/Z
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.
Indexed as
Animalsbeta-Lactamase Inhibitorsbeta-LactamsGram-Negative BacteriaHumansMiceMicrobial Sensitivity TestsProtein BindingStructure-Activity Relationshipbeta-Lactamase Inhibitorsbeta-Lactams
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