Structural basis of metallo-β-lactamase inhibition by captopril stereoisomers
β-Lactams are the most successful antibacterials, but their effectiveness is threatened by resistance, most importantly by production of serine- and metallo-β-lactamases (MBLs). MBLs are of increasing concern because they catalyse the hydrolysis of almost all β-lactam antibiotics, including recent g...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Published: |
American Society for Microbiology
2015
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| _version_ | 1797067146704977920 |
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| author | Brem, J van Berkel, S Zollman, D Lee, S Gileadi, O McHugh, P Walsh, T McDonough, M Schofield, C |
| author_facet | Brem, J van Berkel, S Zollman, D Lee, S Gileadi, O McHugh, P Walsh, T McDonough, M Schofield, C |
| author_sort | Brem, J |
| collection | OXFORD |
| description | β-Lactams are the most successful antibacterials, but their effectiveness is threatened by resistance, most importantly by production of serine- and metallo-β-lactamases (MBLs). MBLs are of increasing concern because they catalyse the hydrolysis of almost all β-lactam antibiotics, including recent generation carbapenems. Clinically useful serine-β-lactamase inhibitors have been developed, but such inhibitors are not available for MBLs. L-Captopril, used to treat hypertension via angiotensin-converting enzyme inhibition, has been reported to inhibit MBLs by chelating to the active site zinc ions via its thiol(ate). We report systematic studies on B1 MBL inhibition by all four captopril stereoisomers. High resolution crystal structures of three MBLs (IMP-1, BcII and VIM-2) in complex with either L-or D-captopril stereoisomers reveal correlations between the binding modes and inhibition potency. The results will be useful in the design of MBL inhibitors with the breadth of selectivity required for clinical application against carbapenem-resistant Enterobacteriaceae and other MBL mediated resistant infections. |
| first_indexed | 2024-03-06T21:52:10Z |
| format | Journal article |
| id | oxford-uuid:4bab557f-d47e-4d91-9d38-01da6cdc7b8c |
| institution | University of Oxford |
| last_indexed | 2024-03-06T21:52:10Z |
| publishDate | 2015 |
| publisher | American Society for Microbiology |
| record_format | dspace |
| spelling | oxford-uuid:4bab557f-d47e-4d91-9d38-01da6cdc7b8c2022-03-26T15:44:53ZStructural basis of metallo-β-lactamase inhibition by captopril stereoisomersJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4bab557f-d47e-4d91-9d38-01da6cdc7b8cSymplectic Elements at OxfordAmerican Society for Microbiology2015Brem, Jvan Berkel, SZollman, DLee, SGileadi, OMcHugh, PWalsh, TMcDonough, MSchofield, Cβ-Lactams are the most successful antibacterials, but their effectiveness is threatened by resistance, most importantly by production of serine- and metallo-β-lactamases (MBLs). MBLs are of increasing concern because they catalyse the hydrolysis of almost all β-lactam antibiotics, including recent generation carbapenems. Clinically useful serine-β-lactamase inhibitors have been developed, but such inhibitors are not available for MBLs. L-Captopril, used to treat hypertension via angiotensin-converting enzyme inhibition, has been reported to inhibit MBLs by chelating to the active site zinc ions via its thiol(ate). We report systematic studies on B1 MBL inhibition by all four captopril stereoisomers. High resolution crystal structures of three MBLs (IMP-1, BcII and VIM-2) in complex with either L-or D-captopril stereoisomers reveal correlations between the binding modes and inhibition potency. The results will be useful in the design of MBL inhibitors with the breadth of selectivity required for clinical application against carbapenem-resistant Enterobacteriaceae and other MBL mediated resistant infections. |
| spellingShingle | Brem, J van Berkel, S Zollman, D Lee, S Gileadi, O McHugh, P Walsh, T McDonough, M Schofield, C Structural basis of metallo-β-lactamase inhibition by captopril stereoisomers |
| title | Structural basis of metallo-β-lactamase inhibition by captopril stereoisomers |
| title_full | Structural basis of metallo-β-lactamase inhibition by captopril stereoisomers |
| title_fullStr | Structural basis of metallo-β-lactamase inhibition by captopril stereoisomers |
| title_full_unstemmed | Structural basis of metallo-β-lactamase inhibition by captopril stereoisomers |
| title_short | Structural basis of metallo-β-lactamase inhibition by captopril stereoisomers |
| title_sort | structural basis of metallo β lactamase inhibition by captopril stereoisomers |
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