Cyclobutanone mimics of intermediates in metallo-β-lactamase catalysis.
The most important resistance mechanism to β-lactam antibiotics involves hydrolysis by two β-lactamase categories: the nucleophilic serine (SBL) and the metallo- (MBL) β-lactamases. Cyclobutanones are hydrolytically stable β-lactam analogues with potential to inhibit both SBLs and MBLs. We describe...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Wiley
2017
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| _version_ | 1826287293822926848 |
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| author | Abboud, M Kosmopoulou, M Krismanich, A Johnson, J Hinchliffe, P Brem, J Claridge, T Spencer, J Schofield, C Dmitrienko, G |
| author_facet | Abboud, M Kosmopoulou, M Krismanich, A Johnson, J Hinchliffe, P Brem, J Claridge, T Spencer, J Schofield, C Dmitrienko, G |
| author_sort | Abboud, M |
| collection | OXFORD |
| description | The most important resistance mechanism to β-lactam antibiotics involves hydrolysis by two β-lactamase categories: the nucleophilic serine (SBL) and the metallo- (MBL) β-lactamases. Cyclobutanones are hydrolytically stable β-lactam analogues with potential to inhibit both SBLs and MBLs. We describe solution and crystallographic studies on the interaction of a cyclobutanone penem analogue with the clinically important MBL SPM-1. NMR experiments using 19F-labeled SPM-1 imply the cyclobutanone binds to SPM-1 with micromolar affinity. A crystal structure of the SPM-1:cyclobutanone complex reveals binding of the hydrated cyclobutanone via interactions with one of the zinc ions, stabilisation of the hydrate by hydrogen bonding to zinc-bound water, and hydrophobic contacts with aromatic residues. NMR analyses using a 13C-labeled cyclobutanone support assignment of the bound species as the hydrated ketone. The results inform on how MBLs bind substrates and stabilize tetrahedral intermediates. They support further investigations on the use of transition state and/or intermediate analogues as inhibitors of all β-lactamase classes. |
| first_indexed | 2024-03-07T01:56:30Z |
| format | Journal article |
| id | oxford-uuid:9be16721-4623-4760-9a1e-f4f110e4809e |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:56:30Z |
| publishDate | 2017 |
| publisher | Wiley |
| record_format | dspace |
| spelling | oxford-uuid:9be16721-4623-4760-9a1e-f4f110e4809e2022-03-27T00:32:13ZCyclobutanone mimics of intermediates in metallo-β-lactamase catalysis.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:9be16721-4623-4760-9a1e-f4f110e4809eEnglishSymplectic Elements at OxfordWiley2017Abboud, MKosmopoulou, MKrismanich, AJohnson, JHinchliffe, PBrem, JClaridge, TSpencer, JSchofield, CDmitrienko, GThe most important resistance mechanism to β-lactam antibiotics involves hydrolysis by two β-lactamase categories: the nucleophilic serine (SBL) and the metallo- (MBL) β-lactamases. Cyclobutanones are hydrolytically stable β-lactam analogues with potential to inhibit both SBLs and MBLs. We describe solution and crystallographic studies on the interaction of a cyclobutanone penem analogue with the clinically important MBL SPM-1. NMR experiments using 19F-labeled SPM-1 imply the cyclobutanone binds to SPM-1 with micromolar affinity. A crystal structure of the SPM-1:cyclobutanone complex reveals binding of the hydrated cyclobutanone via interactions with one of the zinc ions, stabilisation of the hydrate by hydrogen bonding to zinc-bound water, and hydrophobic contacts with aromatic residues. NMR analyses using a 13C-labeled cyclobutanone support assignment of the bound species as the hydrated ketone. The results inform on how MBLs bind substrates and stabilize tetrahedral intermediates. They support further investigations on the use of transition state and/or intermediate analogues as inhibitors of all β-lactamase classes. |
| spellingShingle | Abboud, M Kosmopoulou, M Krismanich, A Johnson, J Hinchliffe, P Brem, J Claridge, T Spencer, J Schofield, C Dmitrienko, G Cyclobutanone mimics of intermediates in metallo-β-lactamase catalysis. |
| title | Cyclobutanone mimics of intermediates in metallo-β-lactamase catalysis. |
| title_full | Cyclobutanone mimics of intermediates in metallo-β-lactamase catalysis. |
| title_fullStr | Cyclobutanone mimics of intermediates in metallo-β-lactamase catalysis. |
| title_full_unstemmed | Cyclobutanone mimics of intermediates in metallo-β-lactamase catalysis. |
| title_short | Cyclobutanone mimics of intermediates in metallo-β-lactamase catalysis. |
| title_sort | cyclobutanone mimics of intermediates in metallo β lactamase catalysis |
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