Academic Journal
Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors
| العنوان: | Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors |
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| المؤلفون: | Brem, Jürgen, Panduwawala, Tharindi, Hansen, Jon Ulf, Hewitt, Joanne, Liepins, Edgars, Donets, Pawel, Espina, Laura, Farley, Alistair J M, Shubin, Kirill, Campillos, Gonzalo Gomez, Kiuru, Paula, Shishodia, Shifali, Krahn, Daniel, Leśniak, Robert K, Schmidt Adrian, Juliane, Calvopiña, Karina, Turrientes, María-Carmen, Kavanagh, Madeline E, Lubriks, Dmitrijs, Hinchliffe, Philip, Langley, Gareth W, Aboklaish, Ali F, Eneroth, Anders, Backlund, Maria, Baran, Andrei G, Nielsen, Elisabet I, Speake, Michael, Kuka, Janis, Robinson, John, Grinberga, Solveiga, Robinson, Lindsay, McDonough, Michael A, Rydzik, Anna M, Leissing, Thomas M, Jimenez-Castellanos, Juan Carlos, Avison, Matthew B, Da Silva Pinto, Solange, Pannifer, Andrew D, Martjuga, Marina, Widlake, Emma, Priede, Martins, Hopkins Navratilova, Iva, Gniadkowski, Marek, Belfrage, Anna Karin, Brandt, Peter, Yli-Kauhaluoma, Jari, Bacque, Eric, Page, Malcolm G P, Björkling, Fredrik, Tyrrell, Jonathan M, Spencer, James, Lang, Pauline A, Baranczewski, Pawel, Cantón, Rafael, McElroy, Stuart P, Jones, Philip S, Baquero, Fernando, Suna, Edgars, Morrison, Angus, Walsh, Timothy R, Schofield, Christopher J |
| المصدر: | Brem , J , Panduwawala , T , Hansen , J U , Hewitt , J , Liepins , E , Donets , P , Espina , L , Farley , A J M , Shubin , K , Campillos , G G , Kiuru , P , Shishodia , S , Krahn , D , Leśniak , R K , Schmidt Adrian , J , Calvopiña , K , Turrientes , M-C , Kavanagh , M E , Lubriks , D , Hinchliffe , P , Langley , G W , Aboklaish , A F , Eneroth , .... |
| سنة النشر: | 2022 |
| المجموعة: | University of Bristol: Bristol Reserach |
| الوصف: | Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-β-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential β-lactamase stable β-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| DOI: | 10.1038/s41557-021-00831-x |
| الاتاحة: | https://hdl.handle.net/1983/793e475d-25fb-4b53-9daf-4f4ab7f70ac3 https://research-information.bris.ac.uk/en/publications/793e475d-25fb-4b53-9daf-4f4ab7f70ac3 https://doi.org/10.1038/s41557-021-00831-x https://research-information.bris.ac.uk/ws/files/323318874/IC_MBLinh_NatChem_accepted.pdf https://research-information.bris.ac.uk/ws/files/323318876/SI_accepted.pdf |
| Rights: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.218871D0 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41557-021-00831-x |
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