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

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

UR - https://www.scopus.com/pages/publications/85061339455

U2 - 10.1016/j.bbagen.2019.02.004

DO - 10.1016/j.bbagen.2019.02.004

M3 - Article

C2 - 30738906

SN - 0304-4165

VL - 1863

SP - 742

EP - 748

JO - BBA - General Subjects

JF - BBA - General Subjects

IS - 4

ER -