Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors

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Brem, Jürgen (author)

Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors

Article/chapterEnglish2022

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2021-12-13
Springer Nature,2022
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LIBRIS-ID:oai:DiVA.org:uu-465165
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-465165URI
https://doi.org/10.1038/s41557-021-00831-xDOI

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Language:English
Summary in:English

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SwePubSwePub

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

Notes

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.

Subject headings and genre

Pharmaceutical Science
Farmaceutisk vetenskap

Added entries (persons, corporate bodies, meetings, titles ...)

Panduwawala, Tharindi (author)
Hansen, Jon Ulf (author)
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)
Eneroth, AndersUppsala universitet,Institutionen för farmaci(Swepub:uu)anden850 (author)
Backlund, MariaUppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab(Swepub:uu)marba192 (author)
Baran, Andrei G (author)
Nielsen, Elisabet I.,1973-Uppsala universitet,Institutionen för farmaci,Institutionen för farmaceutisk biovetenskap(Swepub:uu)elnie838 (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)
Belfrage, Anna Karin,1977-Uppsala universitet,Läkemedelsdesign och läkemedelsutveckling(Swepub:uu)annbe939 (author)
Brandt, PeterUppsala universitet,Läkemedelsdesign och läkemedelsutveckling(Swepub:uu)petbr436 (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)
Baranczewski, PawelUppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab(Swepub:uu)pawba132 (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)
Uppsala universitetInstitutionen för farmaci (creator_code:org_t)

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In:Nature Chemistry: Springer Nature14:1, s. 15-241755-43301755-4349

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By the author/editor: Brem, Jürgen; Panduwawala, Tha ...; Hansen, Jon Ulf; Hewitt, Joanne; Liepins, Edgars; Donets, Pawel; show more...; 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 ...; show less...

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