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

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 - https://www.scopus.com/pages/publications/85121026918

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 -