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Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors
- Brem, Jürgen (author)
- Panduwawala, Tharindi (author)
- Hansen, Jon Ulf (author)
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- Hewitt, Joanne (author)
- Liepins, Edgars (author)
- Donets, Pawel (author)
- Espina, Laura (author)
- Farley, Alistair J M (author)
- Shubin, Kirill (author)
- Campillos, Gonzalo Gomez (author)
- Kiuru, Paula (author)
- Shishodia, Shifali (author)
- Krahn, Daniel (author)
- Leśniak, Robert K (author)
- Schmidt Adrian, Juliane (author)
- Calvopiña, Karina (author)
- Turrientes, María-Carmen (author)
- Kavanagh, Madeline E (author)
- Lubriks, Dmitrijs (author)
- Hinchliffe, Philip (author)
- Langley, Gareth W (author)
- Aboklaish, Ali F (author)
- Baran, Andrei G (author)
- Speake, Michael (author)
- Kuka, Janis (author)
- Robinson, John (author)
- Grinberga, Solveiga (author)
- Robinson, Lindsay (author)
- McDonough, Michael A (author)
- Rydzik, Anna M (author)
- Leissing, Thomas M (author)
- Jimenez-Castellanos, Juan Carlos (author)
- Avison, Matthew B (author)
- Da Silva Pinto, Solange (author)
- Pannifer, Andrew D (author)
- Martjuga, Marina (author)
- Widlake, Emma (author)
- Priede, Martins (author)
- Hopkins Navratilova, Iva (author)
- Gniadkowski, Marek (author)
- Yli-Kauhaluoma, Jari (author)
- Bacque, Eric (author)
- Page, Malcolm G P (author)
- Björkling, Fredrik (author)
- Tyrrell, Jonathan M (author)
- Spencer, James (author)
- Lang, Pauline A (author)
- Cantón, Rafael (author)
- McElroy, Stuart P (author)
- Jones, Philip S (author)
- Baquero, Fernando (author)
- Suna, Edgars (author)
- Morrison, Angus (author)
- Walsh, Timothy R (author)
- Schofield, Christopher J (author)
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- (creator_code:org_t)
- 2021-12-13
- 2022
- English.
- In: Nature Chemistry. - : Springer Nature. - 1755-4330 .- 1755-4349. ; 14:1, s. 15-24
- Journal article (peer-reviewed)
Abstract
Subject headings
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- 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.
Keyword
- Pharmaceutical Science
- Farmaceutisk vetenskap
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- art (subject category)
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- Brem, Jürgen
- Panduwawala, Tha ...
- Hansen, Jon Ulf
- Hewitt, Joanne
- Liepins, Edgars
- Donets, Pawel
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- Espina, Laura
- Farley, Alistair ...
- Shubin, Kirill
- Campillos, Gonza ...
- Kiuru, Paula
- Shishodia, Shifa ...
- Krahn, Daniel
- Leśniak, Robert ...
- Schmidt Adrian, ...
- Calvopiña, Karin ...
- Turrientes, Marí ...
- Kavanagh, Madeli ...
- Lubriks, Dmitrij ...
- Hinchliffe, Phil ...
- Langley, Gareth ...
- Aboklaish, Ali F
- Eneroth, Anders
- Backlund, Maria
- Baran, Andrei G
- Nielsen, Elisabe ...
- Speake, Michael
- Kuka, Janis
- Robinson, John
- Grinberga, Solve ...
- Robinson, Lindsa ...
- McDonough, Micha ...
- Rydzik, Anna M
- Leissing, Thomas ...
- Jimenez-Castella ...
- Avison, Matthew ...
- Da Silva Pinto, ...
- Pannifer, Andrew ...
- Martjuga, Marina
- Widlake, Emma
- Priede, Martins
- Hopkins Navratil ...
- Gniadkowski, Mar ...
- Belfrage, Anna K ...
- Brandt, Peter
- Yli-Kauhaluoma, ...
- Bacque, Eric
- Page, Malcolm G ...
- Björkling, Fredr ...
- Tyrrell, Jonatha ...
- Spencer, James
- Lang, Pauline A
- Baranczewski, Pa ...
- Cantón, Rafael
- McElroy, Stuart ...
- Jones, Philip S
- Baquero, Fernand ...
- Suna, Edgars
- Morrison, Angus
- Walsh, Timothy R
- Schofield, Chris ...
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