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 - http://www.scopus.com/inward/record.url?scp=85061339455&partnerID=8YFLogxK
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 -