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Imitation of ß-lactam binding enables broad-spectrum metallo-ß-lactamase inhibitors.
Brem, Jürgen; Panduwawala, Tharindi; Hansen, Jon Ulf; Hewitt, Joanne; Liepins, Edgars; Donets, Pawel; Espina, Laura; Farley, Alistair J M; Shubin, Kirill; Campillos, Gonzalo Gomez; Kiuru, Paula; Shishodia, Shifali; Krahn, Daniel; Lesniak, Robert K; Schmidt Adrian, Juliane; Calvopiña, Karina; Turrientes, María-Carmen; Kavanagh, Madeline E; Lubriks, Dmitrijs; Hinchliffe, Philip; Langley, Gareth W; Aboklaish, Ali F; Eneroth, Anders; Backlund, Maria; Baran, Andrei G; Nielsen, Elisabet I; Speake, Michael; Kuka, Janis; Robinson, John; Grinberga, Solveiga; Robinson, Lindsay; McDonough, Michael A; Rydzik, Anna M; Leissing, Thomas M; Jimenez-Castellanos, Juan Carlos; Avison, Matthew B; Da Silva Pinto, Solange; Pannifer, Andrew D; Martjuga, Marina; Widlake, Emma; Priede, Martins; Hopkins Navratilova, Iva; Gniadkowski, Marek; Belfrage, Anna Karin; Brandt, Peter; Yli-Kauhaluoma, Jari; Bacque, Eric; Page, Malcolm G P; Björkling, Fredrik; Tyrrell, Jonathan M.
  • Brem J; Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK. jurgen.brem@chem.ox.ac.uk.
  • Panduwawala T; Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
  • Hansen JU; Statens Serum Institut, Copenhagen, Denmark.
  • Hewitt J; University of Dundee, European Screening Centre, BioCity Scotland, Newhouse, UK.
  • Liepins E; Latvian Institute of Organic Synthesis, Riga, Latvia.
  • Donets P; Latvian Institute of Organic Synthesis, Riga, Latvia.
  • Espina L; Department of Medical Microbiology, Institute of infection & Immunity, Cardiff University, Cardiff, UK.
  • Farley AJM; Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
  • Shubin K; Latvian Institute of Organic Synthesis, Riga, Latvia.
  • Campillos GG; Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
  • Kiuru P; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
  • Shishodia S; Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
  • Krahn D; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.
  • Lesniak RK; Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
  • Schmidt Adrian J; Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
  • Calvopiña K; Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
  • Turrientes MC; Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
  • Kavanagh ME; Department of Microbiology, Ramón y Cajal University Hospital and Ramón y Cajal Institute for Health Research (IRYCIS), Madrid, Spain.
  • Lubriks D; Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
  • Hinchliffe P; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • Langley GW; Latvian Institute of Organic Synthesis, Riga, Latvia.
  • Aboklaish AF; School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
  • Eneroth A; Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
  • Backlund M; Charles River Laboratories, Saffron Walden, UK.
  • Baran AG; Department of Medical Microbiology, Institute of infection & Immunity, Cardiff University, Cardiff, UK.
  • Nielsen EI; Department of Pharmacy, Uppsala Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala University, Uppsala, Sweden.
  • Speake M; Department of Pharmacy, Uppsala Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala University, Uppsala, Sweden.
  • Kuka J; Latvian Institute of Organic Synthesis, Riga, Latvia.
  • Robinson J; Department of Pharmacy, Uppsala University, Uppsala, Sweden.
  • Grinberga S; University of Dundee, European Screening Centre, BioCity Scotland, Newhouse, UK.
  • Robinson L; BioAscent Discovery Ltd, Newhouse, UK.
  • McDonough MA; Latvian Institute of Organic Synthesis, Riga, Latvia.
  • Rydzik AM; University of Dundee, European Screening Centre, BioCity Scotland, Newhouse, UK.
  • Leissing TM; BioAscent Discovery Ltd, Newhouse, UK.
  • Jimenez-Castellanos JC; Latvian Institute of Organic Synthesis, Riga, Latvia.
  • Avison MB; University of Dundee, European Screening Centre, BioCity Scotland, Newhouse, UK.
  • Da Silva Pinto S; BioAscent Discovery Ltd, Newhouse, UK.
  • Pannifer AD; Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
  • Martjuga M; Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
  • Widlake E; Research and Early Development, Respiratory & Immunology, AstraZeneca, Mölndal, Sweden.
  • Priede M; Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
  • Hopkins Navratilova I; School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
  • Gniadkowski M; Chemical Biology of Antibiotics, Centre for Infection & Immunity (CIIL), Pasteur Institute, INSERM U1019 - CNRS UMR 9017, Lille, France.
  • Belfrage AK; School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
  • Brandt P; Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
  • Yli-Kauhaluoma J; University of Dundee, European Screening Centre, BioCity Scotland, Newhouse, UK.
  • Bacque E; Latvian Institute of Organic Synthesis, Riga, Latvia.
  • Page MGP; Department of Medical Microbiology, Institute of infection & Immunity, Cardiff University, Cardiff, UK.
  • Björkling F; Latvian Institute of Organic Synthesis, Riga, Latvia.
  • Tyrrell JM; University of Dundee, European Screening Centre, BioCity Scotland, Newhouse, UK.
Nat Chem ; 14(1): 15-24, 2022 01.
Article en En | MEDLINE | ID: mdl-34903857
ABSTRACT
Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-ß-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 ß-lactamase stable ß-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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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Beta-Lactamas / Inhibidores de beta-Lactamasas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Año: 2022 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Beta-Lactamas / Inhibidores de beta-Lactamasas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Año: 2022 Tipo del documento: Article