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

Jürgen Brem; Tharindi Panduwawala; Jon Ulf Hansen; Joanne Hewitt; Edgars Liepins; Pawel Donets; Laura Espina; Alistair Farley; Kirill Shubin; Gonzalo Gomez Campillos; Paula Kiuru; Shifali Shishodia; Daniel Krahn; Rob Lesniak; Juliane Schmidt (Adrian); Karina Calvopina; Maria-Carmen Turrientes; Madeline E. Kavanagh; Dmitrijs Lubriks; Philip Hinchliffe; Gareth Langley; Ali F. Aboklaish; Anders Eneroth; Maria Backlund; Andrei G. Baran; Elisabet Nielsen; Michael Speake; Janis Kuka; John Robinson; Solveiga Grinberga; Lindsay Robinson; Michael McDonough; Anna Rydzik; Thomas Leissing; Juan Carlos Jimenez-Castellanos; Matthew B. Avison; Solange Da Silva Pinto; Andrew D. Pannifer; Marina Martjuga; Emma Widlake; Martins Priede; Iva Hopkins Navratilova; Marek Gniadkowski; Anna Karin Belfrage; Peter Brandt; Jari Yli-Kauhaluoma; Eric Bacque; Malcolm G. P. Page; Fredrik Björkling; Jonathan M. Tyrrell; James Spencer; Pauline A. Lang; Pawel Baranczewski; Rafael Canton; Stuart P. McElroy; Philip S. Jones; Fernando Baquero; Edgars Suna; Angus Morrison; Timothy R. Walsh; Christopher J. Schofield

doi:10.1038/s41557-021-00831-x

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

Jürgen Brem, Tharindi Panduwawala, Jon Ulf Hansen, Joanne Hewitt, Edgars Liepins, Pawel Donets, Laura Espina, Alistair Farley, Kirill Shubin, Gonzalo Gomez Campillos, Paula Kiuru, Shifali Shishodia, Daniel Krahn, Rob Lesniak, Juliane Schmidt (Adrian), Karina Calvopina, Maria-Carmen Turrientes, Madeline E. Kavanagh, Dmitrijs Lubriks, Philip HinchliffeGareth Langley, Ali F. Aboklaish, Anders Eneroth, Maria Backlund, Andrei G. Baran, Elisabet Nielsen, Michael Speake, Janis Kuka, John Robinson, Solveiga Grinberga, Lindsay Robinson, Michael McDonough, Anna Rydzik, Thomas Leissing, Juan Carlos Jimenez-Castellanos, Matthew B. Avison, Solange Da Silva Pinto, Andrew D. Pannifer, Marina Martjuga, Emma Widlake, Martins Priede, Iva Hopkins Navratilova, Marek Gniadkowski, Anna Karin Belfrage, Peter Brandt, Jari Yli-Kauhaluoma, Eric Bacque, Malcolm G. P. Page, Fredrik Björkling, Jonathan M. Tyrrell, James Spencer, Pauline A. Lang, Pawel Baranczewski, Rafael Canton, Stuart P. McElroy, Philip S. Jones, Fernando Baquero, Edgars Suna, Angus Morrison, Timothy R. Walsh, Christopher J. Schofield

Research output: Contribution to journal › Article › Scientific › peer-review

Abstract

Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-beta-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 beta-lactamase stable beta-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.

Original language	English
Journal	Nature Chemistry
Volume	14
Issue number	1
Pages (from-to)	15-24
Number of pages	14
ISSN	1755-4330
DOIs	https://doi.org/10.1038/s41557-021-00831-x
Publication status	Published - 12 Jan 2022
MoE publication type	A1 Journal article-refereed

Fields of Science

AVIBACTAM
MECHANISM
RESISTANCE
ANTIBIOTICS
metallo-beta-lactamase
317 Pharmacy

Access to Document

10.1038/s41557-021-00831-x

Maintext_InC_JB_23-07-2021Accepted author manuscript, 394 KBLicence: Other

European Gram-Negative Antibacterial Engine
Yli-Kauhaluoma, J. (Principal Investigator), Haavikko, R. (Participant), Kiuru, P. (Project manager) & Neal, A. (Participant)
01/02/2014 → 31/01/2020
Project: Research project

Viikki Metabolomics Unit (LS-RIA/ Metabo-HiLIFE)
Sipari, N. (Manager)
Faculty of Biological and Environmental Sciences
Facility/equipment: Core Facility

Cite this

Brem, J., Panduwawala, T., Hansen, J. U., Hewitt, J., Liepins, E., Donets, P., Espina, L., Farley, A., Shubin, K., Gomez Campillos, G., Kiuru, P., Shishodia, S., Krahn, D., Lesniak, R., Schmidt (Adrian), J., Calvopina, K., Turrientes, M.-C., Kavanagh, M. E., Lubriks, D., ... Schofield, C. J. (2022). Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors. Nature Chemistry, 14(1), 15-24. https://doi.org/10.1038/s41557-021-00831-x

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abstract = "Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-beta-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 beta-lactamase stable beta-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.",

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Brem, J, Panduwawala, T, Hansen, JU, Hewitt, J, Liepins, E, Donets, P, Espina, L, Farley, A, Shubin, K, Gomez Campillos, G, Kiuru, P, Shishodia, S, Krahn, D, Lesniak, R, Schmidt (Adrian), J, Calvopina, K, Turrientes, M-C, Kavanagh, ME, Lubriks, D, Hinchliffe, P, Langley, G, Aboklaish, AF, Eneroth, A, Backlund, M, Baran, AG, Nielsen, E, Speake, M, Kuka, J, Robinson, J, Grinberga, S, Robinson, L, McDonough, M, Rydzik, A, Leissing, T, Jimenez-Castellanos, JC, Avison, MB, Da Silva Pinto, S, Pannifer, AD, Martjuga, M, Widlake, E, Priede, M, Hopkins Navratilova, I, Gniadkowski, M, Belfrage, AK, Brandt, P, Yli-Kauhaluoma, J, Bacque, E, Page, MGP, Björkling, F, Tyrrell, JM, Spencer, J, Lang, PA, Baranczewski, P, Canton, R, McElroy, SP, Jones, PS, Baquero, F, Suna, E, Morrison, A, Walsh, TR & Schofield, CJ 2022, 'Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors', Nature Chemistry, vol. 14, no. 1, pp. 15-24. https://doi.org/10.1038/s41557-021-00831-x

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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

AU - Shubin, Kirill

AU - Gomez Campillos, Gonzalo

AU - Kiuru, Paula

AU - Shishodia, Shifali

AU - Krahn, Daniel

AU - Lesniak, Rob

AU - Schmidt (Adrian), Juliane

AU - Calvopina, Karina

AU - Turrientes, Maria-Carmen

AU - Kavanagh, Madeline E.

AU - Lubriks, Dmitrijs

AU - Hinchliffe, Philip

AU - Langley, Gareth

AU - Aboklaish, Ali F.

AU - Eneroth, Anders

AU - Backlund, Maria

AU - Baran, Andrei G.

AU - Nielsen, Elisabet

AU - Speake, Michael

AU - Kuka, Janis

AU - Robinson, John

AU - Grinberga, Solveiga

AU - Robinson, Lindsay

AU - McDonough, Michael

AU - Rydzik, Anna

AU - Leissing, Thomas

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 - Canton, 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.

PY - 2022/1/12

Y1 - 2022/1/12

N2 - Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-beta-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 beta-lactamase stable beta-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.

AB - Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-beta-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 beta-lactamase stable beta-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.

KW - AVIBACTAM

KW - MECHANISM

KW - RESISTANCE

KW - ANTIBIOTICS

KW - metallo-beta-lactamase

KW - 317 Pharmacy

U2 - 10.1038/s41557-021-00831-x

DO - 10.1038/s41557-021-00831-x

M3 - Article

SN - 1755-4330

VL - 14

SP - 15

EP - 24

JO - Nature Chemistry

JF - Nature Chemistry

IS - 1

ER -

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

Abstract

Fields of Science

Access to Document

Projects

European Gram-Negative Antibacterial Engine

Equipment

Viikki Metabolomics Unit (LS-RIA/ Metabo-HiLIFE)

Cite this