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 J. M. Farley; Kirill Shubin; Gonzalo Gomez Campillos; Paula Kiuru; Shifali Shishodia; Daniel Krahn; Robert K. Leśniak; Juliane Schmidt (Adrian); Karina Calvopiña; María-Carmen Turrientes; Madeline E. Kavanagh; Dmitrijs Lubriks; Philip Hinchliffe; Gareth W. Langley; Ali F. Aboklaish; Anders Eneroth; Maria Backlund; Andrei G. Baran; Elisabet I. Nielsen; Michael Speake; Janis Kuka; John Robinson; Solveiga Grinberga; Lindsay Robinson; Michael A. McDonough; Anna M. Rydzik; Thomas M. 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 Cantón; 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 (Lead / Corresponding author), Tharindi Panduwawala, Jon Ulf Hansen, Joanne Hewitt, Edgars Liepins, Pawel Donets, Laura Espina, Alistair J. M. Farley, Kirill Shubin, Gonzalo Gomez Campillos, Paula Kiuru, Shifali Shishodia, Daniel Krahn, Robert K. Leśniak, Juliane Schmidt (Adrian), Karina Calvopiña, María-Carmen Turrientes, Madeline E. Kavanagh, Dmitrijs Lubriks, Philip HinchliffeGareth W. Langley, Ali F. Aboklaish, Anders Eneroth, Maria Backlund, Andrei G. Baran, Elisabet I. Nielsen, Michael Speake, Janis Kuka, John Robinson, Solveiga Grinberga, Lindsay Robinson, Michael A. McDonough, Anna M. Rydzik, Thomas M. 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 Cantón, Stuart P. McElroy, Philip S. Jones, Fernando Baquero, Edgars Suna, Angus Morrison, Timothy R Walsh, Christopher J. Schofield (Lead / Corresponding author)

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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.

Original language	English
Pages (from-to)	15-24
Number of pages	10
Journal	Nature Chemistry
Volume	14
Early online date	13 Dec 2021
DOIs	https://doi.org/10.1038/s41557-021-00831-x
Publication status	Published - Jan 2022

Keywords

Drug discovery and development
Lead optimization
Medicinal chemistry

ASJC Scopus subject areas

General Chemical Engineering
General Chemistry

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10.1038/s41557-021-00831-x

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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., ... Schofield, C. J. (2022). Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors. Nature Chemistry, 14, 15-24. https://doi.org/10.1038/s41557-021-00831-x

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title = "Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors",

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.",

keywords = "Drug discovery and development, Lead optimization, Medicinal chemistry",

author = "J{\"u}rgen Brem and Tharindi Panduwawala and Hansen, {Jon Ulf} and Joanne Hewitt and Edgars Liepins and Pawel Donets and Laura Espina and Farley, {Alistair J. M.} and Kirill Shubin and Campillos, {Gonzalo Gomez} and Paula Kiuru and Shifali Shishodia and Daniel Krahn and Le{\'s}niak, {Robert K.} and {Schmidt (Adrian)}, Juliane and Karina Calvopi{\~n}a and Mar{\'i}a-Carmen Turrientes and Kavanagh, {Madeline E.} and Dmitrijs Lubriks and Philip Hinchliffe and Langley, {Gareth W.} and Aboklaish, {Ali F.} and Anders Eneroth and Maria Backlund and Baran, {Andrei G.} and Nielsen, {Elisabet I.} and Michael Speake and Janis Kuka and John Robinson and Solveiga Grinberga and Lindsay Robinson and McDonough, {Michael A.} and Rydzik, {Anna M.} and Leissing, {Thomas M.} and Jimenez-Castellanos, {Juan Carlos} and Avison, {Matthew B.} and {Da Silva Pinto}, Solange and Pannifer, {Andrew D.} and Marina Martjuga and Emma Widlake and Martins Priede and {Hopkins Navratilova}, Iva and Marek Gniadkowski and Belfrage, {Anna Karin} and Peter Brandt and Jari Yli-Kauhaluoma and Eric Bacque and Page, {Malcolm G. P.} and Fredrik Bj{\"o}rkling and Tyrrell, {Jonathan M.} and James Spencer and Lang, {Pauline A.} and Pawel Baranczewski and Rafael Cant{\'o}n and McElroy, {Stuart P.} and Jones, {Philip S.} and Fernando Baquero and Edgars Suna and Angus Morrison and Walsh, {Timothy R} and Schofield, {Christopher J.}",

note = "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{\textquoteright}s Seventh Framework Programme (FP7/2007–2013), and the EFPIA companies{\textquoteright} 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). {\textcopyright} 2021. The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

month = jan,

doi = "10.1038/s41557-021-00831-x",

language = "English",

volume = "14",

pages = "15--24",

journal = "Nature Chemistry",

issn = "1755-4330",

publisher = "Nature Publishing Group",

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Brem, J, Panduwawala, T, Hansen, JU, Hewitt, J, Liepins, E, Donets, P, Espina, L, Farley, AJM, Shubin, K, Campillos, GG, Kiuru, P, Shishodia, S, Krahn, D, Leśniak, RK, Schmidt (Adrian), J, Calvopiña, K, Turrientes, M-C, Kavanagh, ME, Lubriks, D, Hinchliffe, P, Langley, GW, Aboklaish, AF, Eneroth, A, Backlund, M, Baran, AG, Nielsen, EI, Speake, M, Kuka, J, Robinson, J, Grinberga, S, Robinson, L, McDonough, MA, Rydzik, AM, Leissing, TM, 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, Cantón, 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, pp. 15-24. https://doi.org/10.1038/s41557-021-00831-x

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 - 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). © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2022/1

Y1 - 2022/1

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.

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.

KW - Drug discovery and development

KW - Lead optimization

KW - Medicinal chemistry

UR - http://www.scopus.com/inward/record.url?scp=85121026918&partnerID=8YFLogxK

U2 - 10.1038/s41557-021-00831-x

DO - 10.1038/s41557-021-00831-x

M3 - Article

C2 - 34903857

SN - 1755-4330

VL - 14

SP - 15

EP - 24

JO - Nature Chemistry

JF - Nature Chemistry

ER -

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

Abstract

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

Abstract

Keywords

ASJC Scopus subject areas

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European Lead Factory EUC2LID (IMI) (Joint with 29 other Partners)

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