Samuel T Cahill1, Jonathan M Tyrrell2, Iva Hopkins Navratilova3, Karina Calvopiña4, Sean W Robinson5, Christopher T Lohans1, Michael A McDonough1, Ricky Cain6, Colin W G Fishwick6, Matthew B Avison4, Timothy R Walsh2, Christopher J Schofield7, Jürgen Brem8. 1. Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom. 2. Department of Medical Microbiology & Infectious Disease, Institute of Infection & Immunity, UHW Main Building, Heath Park, Cardiff CF14 4XN, United Kingdom. 3. University of Dundee, Dow Street, Dundee DD1 5EH, United Kingdom; Research Complex at Harwell, Rutherford Appleton Lab, Harwell, Oxford OX11 0FA, United Kingdom. 4. School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, Bristol BS8 1TD, United Kingdom. 5. Kinetic Discovery Ltd, Rutherford Appleton Laboratory, Oxford, Didcot OX11 0FA, United Kingdom. 6. School of Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom. 7. Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom. Electronic address: christopher.schofield@chem.ox.ac.uk. 8. Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom. Electronic address: jurgen.brem@chem.ox.ac.uk.
Abstract
BACKGROUND: The β-lactam antibiotics represent the most successful drug class for treatment of bacterial infections. Resistance to them, importantly via production of β-lactamases, which collectively are able to hydrolyse all classes of β-lactams, threatens their continued widespread use. Bicyclic boronates show potential as broad spectrum inhibitors of the mechanistically distinct serine- (SBL) and metallo- (MBL) β-lactamase families. METHODS: Using biophysical methods, including crystallographic analysis, we have investigated the binding mode of bicyclic boronates to clinically important β-lactamases. Induction experiments and agar-based MIC screening against MDR-Enterobacteriaceae (n = 132) were used to evaluate induction properties and the in vitro efficacy of a bicyclic boronate in combination with meropenem. RESULTS: Crystallographic analysis of a bicyclic boronate in complex with AmpC from Pseudomonas aeruginosa reveals it binds to form a tetrahedral boronate species. Microbiological studies on the clinical coverage (in combination with meropenem) and induction of β-lactamases by bicyclic boronates further support the promise of such compounds as broad spectrum β-lactamase inhibitors. CONCLUSIONS: Together with reported studies on the structural basis of their inhibition of class A, B and D β-lactamases, biophysical studies, including crystallographic analysis, support the proposal that bicyclic boronates mimic tetrahedral intermediates common to SBL and MBL catalysis. GENERAL SIGNIFICANCE: Bicyclic boronates are a new generation of broad spectrum inhibitors of both SBLs and MBLs.
BACKGROUND: The β-lactam antibiotics represent the most successful drug class for treatment of bacterial infections. Resistance to them, importantly via production of β-lactamases, which collectively are able to hydrolyse all classes of β-lactams, threatens their continued widespread use. Bicyclic boronates show potential as broad spectrum inhibitors of the mechanistically distinct serine- (SBL) and metallo- (MBL) β-lactamase families. METHODS: Using biophysical methods, including crystallographic analysis, we have investigated the binding mode of bicyclic boronates to clinically important β-lactamases. Induction experiments and agar-based MIC screening against MDR-Enterobacteriaceae (n = 132) were used to evaluate induction properties and the in vitro efficacy of a bicyclic boronate in combination with meropenem. RESULTS: Crystallographic analysis of a bicyclic boronate in complex with AmpC from Pseudomonas aeruginosa reveals it binds to form a tetrahedral boronate species. Microbiological studies on the clinical coverage (in combination with meropenem) and induction of β-lactamases by bicyclic boronates further support the promise of such compounds as broad spectrum β-lactamase inhibitors. CONCLUSIONS: Together with reported studies on the structural basis of their inhibition of class A, B and D β-lactamases, biophysical studies, including crystallographic analysis, support the proposal that bicyclic boronates mimic tetrahedral intermediates common to SBL and MBL catalysis. GENERAL SIGNIFICANCE: Bicyclic boronates are a new generation of broad spectrum inhibitors of both SBLs and MBLs.
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: Nat Chem Date: 2021-12-13 Impact factor: 24.427
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Authors: Scott T Lefurgy; Emilia Caselli; Magdalena A Taracila; Vladimir N Malashkevich; Beena Biju; Krisztina M Papp-Wallace; Jeffrey B Bonanno; Fabio Prati; Steven C Almo; Robert A Bonomo Journal: Biomolecules Date: 2020-04-27
Authors: Alen Krajnc; Jürgen Brem; Philip Hinchliffe; Karina Calvopiña; Tharindi D Panduwawala; Pauline A Lang; Jos J A G Kamps; Jonathan M Tyrrell; Emma Widlake; Benjamin G Saward; Timothy R Walsh; James Spencer; Christopher J Schofield Journal: J Med Chem Date: 2019-09-16 Impact factor: 7.446
Authors: Catherine L Tooke; Philip Hinchliffe; Alen Krajnc; Adrian J Mulholland; Jürgen Brem; Christopher J Schofield; James Spencer Journal: RSC Med Chem Date: 2020-01-10
Authors: Kamaleddin H M E Tehrani; Nora C Brüchle; Nicola Wade; Vida Mashayekhi; Diego Pesce; Matthijs J van Haren; Nathaniel I Martin Journal: ACS Infect Dis Date: 2020-04-03 Impact factor: 5.084
Authors: Pauline A Lang; Anete Parkova; Thomas M Leissing; Karina Calvopiña; Ricky Cain; Alen Krajnc; Tharindi D Panduwawala; Jules Philippe; Colin W G Fishwick; Peteris Trapencieris; Malcolm G P Page; Christopher J Schofield; Jürgen Brem Journal: Biomolecules Date: 2020-06-12