Studies on the inhibition of AmpC and other β-lactamases by cyclic boronates
<strong>Background</strong> 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 continue...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal article |
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Elsevier
2019
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| _version_ | 1826297867492392960 |
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| author | Cahill, S Tyrrell, J Navratilovac, I Calvopiña, K Robinson, S Lohans, C McDonough, M Cain, R Fishwick, C Avison, M Walsh, T Schofield, C Brem, J |
| author_facet | Cahill, S Tyrrell, J Navratilovac, I Calvopiña, K Robinson, S Lohans, C McDonough, M Cain, R Fishwick, C Avison, M Walsh, T Schofield, C Brem, J |
| author_sort | Cahill, S |
| collection | OXFORD |
| description | <strong>Background</strong> 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. <br/><br/> <strong>Methods</strong> 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. <br/><br/> <strong>Results</strong> 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. <br/><br/> <strong>Conclusions</strong> 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. |
| first_indexed | 2024-03-07T04:38:10Z |
| format | Journal article |
| id | oxford-uuid:d0b248be-babf-4e08-b26a-51e049334873 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T04:38:10Z |
| publishDate | 2019 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:d0b248be-babf-4e08-b26a-51e0493348732022-03-27T07:51:50ZStudies on the inhibition of AmpC and other β-lactamases by cyclic boronatesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d0b248be-babf-4e08-b26a-51e049334873Symplectic Elements at OxfordElsevier2019Cahill, STyrrell, JNavratilovac, ICalvopiña, KRobinson, SLohans, CMcDonough, MCain, RFishwick, CAvison, MWalsh, TSchofield, CBrem, J<strong>Background</strong> 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. <br/><br/> <strong>Methods</strong> 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. <br/><br/> <strong>Results</strong> 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. <br/><br/> <strong>Conclusions</strong> 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. |
| spellingShingle | Cahill, S Tyrrell, J Navratilovac, I Calvopiña, K Robinson, S Lohans, C McDonough, M Cain, R Fishwick, C Avison, M Walsh, T Schofield, C Brem, J Studies on the inhibition of AmpC and other β-lactamases by cyclic boronates |
| title | Studies on the inhibition of AmpC and other β-lactamases by cyclic boronates |
| title_full | Studies on the inhibition of AmpC and other β-lactamases by cyclic boronates |
| title_fullStr | Studies on the inhibition of AmpC and other β-lactamases by cyclic boronates |
| title_full_unstemmed | Studies on the inhibition of AmpC and other β-lactamases by cyclic boronates |
| title_short | Studies on the inhibition of AmpC and other β-lactamases by cyclic boronates |
| title_sort | studies on the inhibition of ampc and other β lactamases by cyclic boronates |
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