In silico fragment based design identifies subfamily B1 metallo-β-lactamase inhibitors
<p>Zinc ion dependent β-lactamases (MBLs) catalyze the hydrolysis of almost all β-lactam antibiotics and resist the action of clinically available β-lactamase inhibitors. We report how application of <i>in silico</i> fragment-based molecular design employing thiol-mediated metal a...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Chemical Society
2017
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| _version_ | 1826256865713979392 |
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| author | Cain, R Brem, J Zollman, D McDonough, M Johnson, R Spencer, J Makena, A Abboud, M Cahill, S Lee, S McHugh, P Schofield, C Fishwick, C |
| author_facet | Cain, R Brem, J Zollman, D McDonough, M Johnson, R Spencer, J Makena, A Abboud, M Cahill, S Lee, S McHugh, P Schofield, C Fishwick, C |
| author_sort | Cain, R |
| collection | OXFORD |
| description | <p>Zinc ion dependent β-lactamases (MBLs) catalyze the hydrolysis of almost all β-lactam antibiotics and resist the action of clinically available β-lactamase inhibitors. We report how application of <i>in silico</i> fragment-based molecular design employing thiol-mediated metal anchorage leads to potent MBL inhibitors. The new inhibitors manifest potent inhibition of clinically important B1 subfamily MBLs, including the widespread NDM-1, IMP-1 and VIM-2 enzymes; with lower potency, some of them also inhibit clinically relevant Class A and D serine-β-lactamases. The inhibitors show selectivity for bacterial MBL enzymes compared to human MBL fold nucleases. Co-crystallization of one inhibitor, which shows potentiation of meropenem activity against MBL-expressing <i>Enterobacteriaceae</i>, with VIM-2 reveals an unexpected binding mode, involving interactions with residues from conserved active site bordering loops.</p> |
| first_indexed | 2024-03-06T18:09:03Z |
| format | Journal article |
| id | oxford-uuid:025dfcb6-e3f9-449a-827b-8c17a7c42b90 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:09:03Z |
| publishDate | 2017 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:025dfcb6-e3f9-449a-827b-8c17a7c42b902022-03-26T08:40:21ZIn silico fragment based design identifies subfamily B1 metallo-β-lactamase inhibitorsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:025dfcb6-e3f9-449a-827b-8c17a7c42b90EnglishSymplectic Elements at OxfordAmerican Chemical Society2017Cain, RBrem, JZollman, DMcDonough, MJohnson, RSpencer, JMakena, AAbboud, MCahill, SLee, SMcHugh, PSchofield, CFishwick, C <p>Zinc ion dependent β-lactamases (MBLs) catalyze the hydrolysis of almost all β-lactam antibiotics and resist the action of clinically available β-lactamase inhibitors. We report how application of <i>in silico</i> fragment-based molecular design employing thiol-mediated metal anchorage leads to potent MBL inhibitors. The new inhibitors manifest potent inhibition of clinically important B1 subfamily MBLs, including the widespread NDM-1, IMP-1 and VIM-2 enzymes; with lower potency, some of them also inhibit clinically relevant Class A and D serine-β-lactamases. The inhibitors show selectivity for bacterial MBL enzymes compared to human MBL fold nucleases. Co-crystallization of one inhibitor, which shows potentiation of meropenem activity against MBL-expressing <i>Enterobacteriaceae</i>, with VIM-2 reveals an unexpected binding mode, involving interactions with residues from conserved active site bordering loops.</p> |
| spellingShingle | Cain, R Brem, J Zollman, D McDonough, M Johnson, R Spencer, J Makena, A Abboud, M Cahill, S Lee, S McHugh, P Schofield, C Fishwick, C In silico fragment based design identifies subfamily B1 metallo-β-lactamase inhibitors |
| title | In silico fragment based design identifies subfamily B1 metallo-β-lactamase inhibitors |
| title_full | In silico fragment based design identifies subfamily B1 metallo-β-lactamase inhibitors |
| title_fullStr | In silico fragment based design identifies subfamily B1 metallo-β-lactamase inhibitors |
| title_full_unstemmed | In silico fragment based design identifies subfamily B1 metallo-β-lactamase inhibitors |
| title_short | In silico fragment based design identifies subfamily B1 metallo-β-lactamase inhibitors |
| title_sort | in silico fragment based design identifies subfamily b1 metallo β lactamase inhibitors |
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