Studies on the Reactions of Biapenem with VIM Metallo β-Lactamases and the Serine β-Lactamase KPC-2
Carbapenems are important antibacterials and are both substrates and inhibitors of some β-lactamases. We report studies on the reaction of the unusual carbapenem biapenem, with the subclass B1 metallo-β-lactamases VIM-1 and VIM-2 and the class A serine-β-lactamase KPC-2. X-ray diffraction studies wi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-03-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/11/3/396 |
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| author | Anka Lucic Tika R. Malla Karina Calvopiña Catherine L. Tooke Jürgen Brem Michael A. McDonough James Spencer Christopher J. Schofield |
| author_facet | Anka Lucic Tika R. Malla Karina Calvopiña Catherine L. Tooke Jürgen Brem Michael A. McDonough James Spencer Christopher J. Schofield |
| author_sort | Anka Lucic |
| collection | DOAJ |
| description | Carbapenems are important antibacterials and are both substrates and inhibitors of some β-lactamases. We report studies on the reaction of the unusual carbapenem biapenem, with the subclass B1 metallo-β-lactamases VIM-1 and VIM-2 and the class A serine-β-lactamase KPC-2. X-ray diffraction studies with VIM-2 crystals treated with biapenem reveal the opening of the β-lactam ring to form a mixture of the (2<i>S</i>)-imine and enamine complexed at the active site. NMR studies on the reactions of biapenem with VIM-1, VIM-2, and KPC-2 reveal the formation of hydrolysed enamine and (2<i>R</i>)- and (2<i>S</i>)-imine products. The combined results support the proposal that SBL/MBL-mediated carbapenem hydrolysis results in a mixture of tautomerizing enamine and (2<i>R</i>)- and (2<i>S</i>)-imine products, with the thermodynamically favoured (2<i>S</i>)-imine being the major observed species over a relatively long-time scale. The results suggest that prolonging the lifetimes of β-lactamase carbapenem complexes by optimising tautomerisation of the nascently formed enamine to the (2<i>R</i>)-imine and likely more stable (2<i>S</i>)-imine tautomer is of interest in developing improved carbapenems. |
| first_indexed | 2024-03-09T20:11:45Z |
| format | Article |
| id | doaj.art-8730b4a5f64843a4aabb65b739538a10 |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-09T20:11:45Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-8730b4a5f64843a4aabb65b739538a102023-11-24T00:11:56ZengMDPI AGAntibiotics2079-63822022-03-0111339610.3390/antibiotics11030396Studies on the Reactions of Biapenem with VIM Metallo β-Lactamases and the Serine β-Lactamase KPC-2Anka Lucic0Tika R. Malla1Karina Calvopiña2Catherine L. Tooke3Jürgen Brem4Michael A. McDonough5James Spencer6Christopher J. Schofield7Chemistry Research Laboratory, The Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3TA, UKChemistry Research Laboratory, The Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3TA, UKChemistry Research Laboratory, The Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3TA, UKBiomedical Sciences Building, School of Cellular and Molecular Medicine, Faculty of Life Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UKChemistry Research Laboratory, The Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3TA, UKChemistry Research Laboratory, The Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3TA, UKBiomedical Sciences Building, School of Cellular and Molecular Medicine, Faculty of Life Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UKChemistry Research Laboratory, The Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford OX1 3TA, UKCarbapenems are important antibacterials and are both substrates and inhibitors of some β-lactamases. We report studies on the reaction of the unusual carbapenem biapenem, with the subclass B1 metallo-β-lactamases VIM-1 and VIM-2 and the class A serine-β-lactamase KPC-2. X-ray diffraction studies with VIM-2 crystals treated with biapenem reveal the opening of the β-lactam ring to form a mixture of the (2<i>S</i>)-imine and enamine complexed at the active site. NMR studies on the reactions of biapenem with VIM-1, VIM-2, and KPC-2 reveal the formation of hydrolysed enamine and (2<i>R</i>)- and (2<i>S</i>)-imine products. The combined results support the proposal that SBL/MBL-mediated carbapenem hydrolysis results in a mixture of tautomerizing enamine and (2<i>R</i>)- and (2<i>S</i>)-imine products, with the thermodynamically favoured (2<i>S</i>)-imine being the major observed species over a relatively long-time scale. The results suggest that prolonging the lifetimes of β-lactamase carbapenem complexes by optimising tautomerisation of the nascently formed enamine to the (2<i>R</i>)-imine and likely more stable (2<i>S</i>)-imine tautomer is of interest in developing improved carbapenems.https://www.mdpi.com/2079-6382/11/3/396carbapenemsantimicrobial resistancemetallo-β-lactamasesserine-β-lactamasesbiapenem |
| spellingShingle | Anka Lucic Tika R. Malla Karina Calvopiña Catherine L. Tooke Jürgen Brem Michael A. McDonough James Spencer Christopher J. Schofield Studies on the Reactions of Biapenem with VIM Metallo β-Lactamases and the Serine β-Lactamase KPC-2 Antibiotics carbapenems antimicrobial resistance metallo-β-lactamases serine-β-lactamases biapenem |
| title | Studies on the Reactions of Biapenem with VIM Metallo β-Lactamases and the Serine β-Lactamase KPC-2 |
| title_full | Studies on the Reactions of Biapenem with VIM Metallo β-Lactamases and the Serine β-Lactamase KPC-2 |
| title_fullStr | Studies on the Reactions of Biapenem with VIM Metallo β-Lactamases and the Serine β-Lactamase KPC-2 |
| title_full_unstemmed | Studies on the Reactions of Biapenem with VIM Metallo β-Lactamases and the Serine β-Lactamase KPC-2 |
| title_short | Studies on the Reactions of Biapenem with VIM Metallo β-Lactamases and the Serine β-Lactamase KPC-2 |
| title_sort | studies on the reactions of biapenem with vim metallo β lactamases and the serine β lactamase kpc 2 |
| topic | carbapenems antimicrobial resistance metallo-β-lactamases serine-β-lactamases biapenem |
| url | https://www.mdpi.com/2079-6382/11/3/396 |
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