Studies on the inhibition of AmpC and other β-lactamases by cyclic boronates

Samuel T. Cahill, Jonathan M. Tyrrell, Iva Hopkins Navratilova, Karina Calvopiña, Sean W. Robinson, Christopher T Lohans, Michael A. McDonough, Ricky Cain, Colin W. G. Fishwick, Matthew B. Avison, Timothy R. Walsh, Christopher J. Schofield (Lead / Corresponding author), Jürgen Brem

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)742-748
Number of pages7
JournalBiochimica et Biophysica Acta: General Subjects
Volume1863
Issue number4
Early online date7 Feb 2019
DOIs
Publication statusPublished - 1 Apr 2019

Fingerprint

meropenem
Lactams
Enterobacteriaceae
Catalysis
Bacterial Infections
Pseudomonas aeruginosa
Serine
Agar
Screening
Anti-Bacterial Agents
Pharmaceutical Preparations
Experiments

Keywords

  • Antimicrobial clinical coverage
  • Cyclic boronate inhibitors
  • Metallo and serine β-lactamase inhibition
  • Transition state analogue
  • β-lactam antibiotic resistance
  • β-lactamase induction

Cite this

Cahill, Samuel T. ; Tyrrell, Jonathan M. ; Navratilova, Iva Hopkins ; Calvopiña, Karina ; Robinson, Sean W. ; Lohans, Christopher T ; McDonough, Michael A. ; Cain, Ricky ; Fishwick, Colin W. G. ; Avison, Matthew B. ; Walsh, Timothy R. ; Schofield, Christopher J. ; Brem, Jürgen. / Studies on the inhibition of AmpC and other β-lactamases by cyclic boronates. In: Biochimica et Biophysica Acta: General Subjects. 2019 ; Vol. 1863, No. 4. pp. 742-748.
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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.",
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note = "We thank the Medical Research Council, the SWON alliance (MR/N002679/1), the SAMRC-Newton grant, the Wellcome Trust, and the European Gram-Negative Antibacterial Engine (ENABLE) for funding our MBL work.",
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Cahill, ST, Tyrrell, JM, Navratilova, IH, Calvopiña, K, Robinson, SW, Lohans, CT, McDonough, MA, Cain, R, Fishwick, CWG, Avison, MB, Walsh, TR, Schofield, CJ & Brem, J 2019, 'Studies on the inhibition of AmpC and other β-lactamases by cyclic boronates', Biochimica et Biophysica Acta: General Subjects, vol. 1863, no. 4, pp. 742-748. https://doi.org/10.1016/j.bbagen.2019.02.004

Studies on the inhibition of AmpC and other β-lactamases by cyclic boronates. / Cahill, Samuel T.; Tyrrell, Jonathan M.; Navratilova, Iva Hopkins; Calvopiña, Karina; Robinson, Sean W.; Lohans, Christopher T; McDonough, Michael A.; Cain, Ricky; Fishwick, Colin W. G.; Avison, Matthew B.; Walsh, Timothy R.; Schofield, Christopher J. (Lead / Corresponding author); Brem, Jürgen.

In: Biochimica et Biophysica Acta: General Subjects, Vol. 1863, No. 4, 01.04.2019, p. 742-748.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Studies on the inhibition of AmpC and other β-lactamases by cyclic boronates

AU - Cahill, Samuel T.

AU - Tyrrell, Jonathan M.

AU - Navratilova, Iva Hopkins

AU - Calvopiña, Karina

AU - Robinson, Sean W.

AU - Lohans, Christopher T

AU - McDonough, Michael A.

AU - Cain, Ricky

AU - Fishwick, Colin W. G.

AU - Avison, Matthew B.

AU - Walsh, Timothy R.

AU - Schofield, Christopher J.

AU - Brem, Jürgen

N1 - We thank the Medical Research Council, the SWON alliance (MR/N002679/1), the SAMRC-Newton grant, the Wellcome Trust, and the European Gram-Negative Antibacterial Engine (ENABLE) for funding our MBL work.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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.

AB - 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.

KW - Antimicrobial clinical coverage

KW - Cyclic boronate inhibitors

KW - Metallo and serine β-lactamase inhibition

KW - Transition state analogue

KW - β-lactam antibiotic resistance

KW - β-lactamase induction

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U2 - 10.1016/j.bbagen.2019.02.004

DO - 10.1016/j.bbagen.2019.02.004

M3 - Article

VL - 1863

SP - 742

EP - 748

JO - Biochimica et Biophysica Acta: General Subjects

JF - Biochimica et Biophysica Acta: General Subjects

SN - 0304-4165

IS - 4

ER -