Abstract
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. [Figure not available: see fulltext.]
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature Chemistry |
| Vol/bind | 14 |
| Sider (fra-til) | 15–24 |
| ISSN | 1755-4330 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Publisher Copyright:© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
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I: Nature Chemistry, Bind 14, 2022, s. 15–24.
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review
}
TY - JOUR
T1 - Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors
AU - Brem, Jürgen
AU - Panduwawala, Tharindi
AU - Hansen, Jon Ulf
AU - Hewitt, Joanne
AU - Liepins, Edgars
AU - Donets, Pawel
AU - Espina, Laura
AU - Farley, Alistair J.M.
AU - Shubin, Kirill
AU - Campillos, Gonzalo Gomez
AU - Kiuru, Paula
AU - Shishodia, Shifali
AU - Krahn, Daniel
AU - Leśniak, Robert K.
AU - Schmidt (Adrian), Juliane
AU - Calvopiña, Karina
AU - Turrientes, María Carmen
AU - Kavanagh, Madeline E.
AU - Lubriks, Dmitrijs
AU - Hinchliffe, Philip
AU - Langley, Gareth W.
AU - Aboklaish, Ali F.
AU - Eneroth, Anders
AU - Backlund, Maria
AU - Baran, Andrei G.
AU - Nielsen, Elisabet I.
AU - Speake, Michael
AU - Kuka, Janis
AU - Robinson, John
AU - Grinberga, Solveiga
AU - Robinson, Lindsay
AU - McDonough, Michael A.
AU - Rydzik, Anna M.
AU - Leissing, Thomas M.
AU - Jimenez-Castellanos, Juan Carlos
AU - Avison, Matthew B.
AU - Da Silva Pinto, Solange
AU - Pannifer, Andrew D.
AU - Martjuga, Marina
AU - Widlake, Emma
AU - Priede, Martins
AU - Hopkins Navratilova, Iva
AU - Gniadkowski, Marek
AU - Belfrage, Anna Karin
AU - Brandt, Peter
AU - Yli-Kauhaluoma, Jari
AU - Bacque, Eric
AU - Page, Malcolm G.P.
AU - Björkling, Fredrik
AU - Tyrrell, Jonathan M.
AU - Spencer, James
AU - Lang, Pauline A.
AU - Baranczewski, Pawel
AU - Cantón, Rafael
AU - McElroy, Stuart P.
AU - Jones, Philip S.
AU - Baquero, Fernando
AU - Suna, Edgars
AU - Morrison, Angus
AU - Walsh, Timothy R.
AU - Schofield, Christopher J.
N1 - Funding Information: We thank the ELF Screening partners for efforts leading to the initial hits, the current and past ENABLE Portfolio Management Committee (PMC) members and EFPIA partners for guidance, and the Diamond Light Source synchrotron for access to the IO3, IO4 and IO4-1 beamlines. J.U.H. thanks N. Sipari from the Viikki Metabolomics Unit (Helsinki Institute of Life Science, University of Helsinki and Biocenter Finland) for her expertise with the liquid chromatography–mass spectroscopy analyses. L.E. thanks Y. Zhou for help in the laboratory, and H. Saif, R. Farzana, E. Portal, K. Sands, K. Thomson and B. Hassan for providing strains for the Enterobacterales collection. The ELF work and the ENABLE project that led to these results were supported by the Innovative Medicines Initiative Joint Undertaking (grant agreements no. 115489 and no. 115583), which have financial contributions from the European Union’s Seventh Framework Programme (FP7/2007–2013), and the EFPIA companies’ in-kind contributions. The ENABLE project is financially supported by contributions from Academic and SME partners. The Oxford work was also supported by Cancer Research UK (C9047/ A24759), the Medical Research Council, the Biotechnology and Biological Research Council (BB/S50676X/1) and the Ineos Oxford Institute for Antimicrobial Research (C.J.S.). This research was funded in whole, or in part, by the Wellcome Trust (grant no. 106244/Z/14/Z and no. 099141/Z/12/Z). The Bristol work was also supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) grant R01AI100560 (J.S. and P.H.) (the content is the responsibility of the authors and does not necessarily represent official views of the NIH) and the BrisSynBio Biosuite (UK Biotechnology and Biological Sciences (BBSRC) and Engineering and Physical Sciences (EPSRC) Research Councils (BB/L01386X/1) and BBSRC ALERT14 initiative (BB/M012107/1). Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022
Y1 - 2022
N2 - 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. [Figure not available: see fulltext.]
AB - 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. [Figure not available: see fulltext.]
U2 - 10.1038/s41557-021-00831-x
DO - 10.1038/s41557-021-00831-x
M3 - Journal article
C2 - 34903857
AN - SCOPUS:85121026918
SN - 1755-4330
VL - 14
SP - 15
EP - 24
JO - Nature Chemistry
JF - Nature Chemistry
ER -