Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates
β-Lactamases enable resistance to almost all β-lactam antibiotics. Pioneering work revealed that acyclic boronic acids can act as 'transition state analogue' inhibitors of nucleophilic serine enzymes, including serine-β-lactamases. Here we report biochemical and biophysical analyses reveal...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Nature Publishing Group
2016
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| _version_ | 1826305296512843776 |
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| author | Brem, J Cain, R Cahill, S McDonough, M Clifton, I Jiménez-Castellanos, J Avison, M Spencer, J Fishwick, C Schofield, C |
| author_facet | Brem, J Cain, R Cahill, S McDonough, M Clifton, I Jiménez-Castellanos, J Avison, M Spencer, J Fishwick, C Schofield, C |
| author_sort | Brem, J |
| collection | OXFORD |
| description | β-Lactamases enable resistance to almost all β-lactam antibiotics. Pioneering work revealed that acyclic boronic acids can act as 'transition state analogue' inhibitors of nucleophilic serine enzymes, including serine-β-lactamases. Here we report biochemical and biophysical analyses revealing that cyclic boronates potently inhibit both nucleophilic serine and zinc-dependent β-lactamases by a mechanism involving mimicking of the common tetrahedral intermediate. Cyclic boronates also potently inhibit the non-essential penicillin-binding protein PBP 5 by the same mechanism of action. The results open the way for development of dual action inhibitors effective against both serine- and metallo-β-lactamases, and which could also have antimicrobial activity through inhibition of PBPs. |
| first_indexed | 2024-03-07T06:30:46Z |
| format | Journal article |
| id | oxford-uuid:f5ea00e0-615e-4ac0-adbc-38417e4a0458 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:30:46Z |
| publishDate | 2016 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:f5ea00e0-615e-4ac0-adbc-38417e4a04582022-03-27T12:30:59ZStructural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronatesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f5ea00e0-615e-4ac0-adbc-38417e4a0458EnglishSymplectic Elements at OxfordNature Publishing Group2016Brem, JCain, RCahill, SMcDonough, MClifton, IJiménez-Castellanos, JAvison, MSpencer, JFishwick, CSchofield, Cβ-Lactamases enable resistance to almost all β-lactam antibiotics. Pioneering work revealed that acyclic boronic acids can act as 'transition state analogue' inhibitors of nucleophilic serine enzymes, including serine-β-lactamases. Here we report biochemical and biophysical analyses revealing that cyclic boronates potently inhibit both nucleophilic serine and zinc-dependent β-lactamases by a mechanism involving mimicking of the common tetrahedral intermediate. Cyclic boronates also potently inhibit the non-essential penicillin-binding protein PBP 5 by the same mechanism of action. The results open the way for development of dual action inhibitors effective against both serine- and metallo-β-lactamases, and which could also have antimicrobial activity through inhibition of PBPs. |
| spellingShingle | Brem, J Cain, R Cahill, S McDonough, M Clifton, I Jiménez-Castellanos, J Avison, M Spencer, J Fishwick, C Schofield, C Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates |
| title | Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates |
| title_full | Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates |
| title_fullStr | Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates |
| title_full_unstemmed | Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates |
| title_short | Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates |
| title_sort | structural basis of metallo β lactamase serine β lactamase and penicillin binding protein inhibition by cyclic boronates |
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