In vitro and in vivo activity of ML302F: a thioenolate inhibitor of VIM-subfamily metallo β-lactamases
The thioenol ML302F was recently identified as an inhibitor of class B metallo-β-lactamases (MBLs). We assessed the activity of ML302F when combined with meropenem (MEM) against 31 carbapenem resistant Gram-negative clinical isolates. Minimum inhibitory concentrations of MEM:ML302F were determined a...
| Главные авторы: | , , , , , , |
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| Формат: | Journal article |
| Опубликовано: |
Royal Society of Chemistry
2015
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| _version_ | 1826294662693912576 |
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| author | Betts, J Phee, L Abdul Momin, M Umland, K Brem, J Schofield, C Wareham, D |
| author_facet | Betts, J Phee, L Abdul Momin, M Umland, K Brem, J Schofield, C Wareham, D |
| author_sort | Betts, J |
| collection | OXFORD |
| description | The thioenol ML302F was recently identified as an inhibitor of class B metallo-β-lactamases (MBLs). We assessed the activity of ML302F when combined with meropenem (MEM) against 31 carbapenem resistant Gram-negative clinical isolates. Minimum inhibitory concentrations of MEM:ML302F were determined at fixed ratios of 1:4 and 1 8 using strains producing variants of the clinically relevant VIM-like MBL. Toxicity and efficacy in vivo was assessed in a Galleria mellonella invertebrate model against strains producing VIM-1, VIM-2 and VIM-4 variants. At a fixed MEM:ML302F ratio of 1:8, 22/31 isolates were rendered either susceptible (MIC ≤ 2 mg L-1), or intermediate (MIC 4-8 mg L-1) to MEM. ML302F alone was not toxic at up to 80 mg kg-1 in G. mellonella and treatment with MEM 0.6 mg kg-1:ML302F 4.8 mg kg-1 significantly improved the survival of infected larvae. As ML302F was able to successfully restore susceptibility to resistant strains both in vitro and in vivo it represents a structurally interesting inhibitor in the search for new MBL inhibitors. |
| first_indexed | 2024-03-07T03:49:09Z |
| format | Journal article |
| id | oxford-uuid:c09e4f5f-819f-4b3f-876d-bd8800b5df41 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T03:49:09Z |
| publishDate | 2015 |
| publisher | Royal Society of Chemistry |
| record_format | dspace |
| spelling | oxford-uuid:c09e4f5f-819f-4b3f-876d-bd8800b5df412022-03-27T05:55:38ZIn vitro and in vivo activity of ML302F: a thioenolate inhibitor of VIM-subfamily metallo β-lactamasesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:c09e4f5f-819f-4b3f-876d-bd8800b5df41Symplectic Elements at OxfordRoyal Society of Chemistry2015Betts, JPhee, LAbdul Momin, MUmland, KBrem, JSchofield, CWareham, DThe thioenol ML302F was recently identified as an inhibitor of class B metallo-β-lactamases (MBLs). We assessed the activity of ML302F when combined with meropenem (MEM) against 31 carbapenem resistant Gram-negative clinical isolates. Minimum inhibitory concentrations of MEM:ML302F were determined at fixed ratios of 1:4 and 1 8 using strains producing variants of the clinically relevant VIM-like MBL. Toxicity and efficacy in vivo was assessed in a Galleria mellonella invertebrate model against strains producing VIM-1, VIM-2 and VIM-4 variants. At a fixed MEM:ML302F ratio of 1:8, 22/31 isolates were rendered either susceptible (MIC ≤ 2 mg L-1), or intermediate (MIC 4-8 mg L-1) to MEM. ML302F alone was not toxic at up to 80 mg kg-1 in G. mellonella and treatment with MEM 0.6 mg kg-1:ML302F 4.8 mg kg-1 significantly improved the survival of infected larvae. As ML302F was able to successfully restore susceptibility to resistant strains both in vitro and in vivo it represents a structurally interesting inhibitor in the search for new MBL inhibitors. |
| spellingShingle | Betts, J Phee, L Abdul Momin, M Umland, K Brem, J Schofield, C Wareham, D In vitro and in vivo activity of ML302F: a thioenolate inhibitor of VIM-subfamily metallo β-lactamases |
| title | In vitro and in vivo activity of ML302F: a thioenolate inhibitor of VIM-subfamily metallo β-lactamases |
| title_full | In vitro and in vivo activity of ML302F: a thioenolate inhibitor of VIM-subfamily metallo β-lactamases |
| title_fullStr | In vitro and in vivo activity of ML302F: a thioenolate inhibitor of VIM-subfamily metallo β-lactamases |
| title_full_unstemmed | In vitro and in vivo activity of ML302F: a thioenolate inhibitor of VIM-subfamily metallo β-lactamases |
| title_short | In vitro and in vivo activity of ML302F: a thioenolate inhibitor of VIM-subfamily metallo β-lactamases |
| title_sort | in vitro and in vivo activity of ml302f a thioenolate inhibitor of vim subfamily metallo β lactamases |
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