Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors PMID: 34903857

ADC Targets in Oncology

2026-04-10

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

Nat Chem. 2022 Jan;14(1):15-24. doi: 10.1038/s41557-021-00831-x.

Jürgen Brem ¹ , Tharindi Panduwawala ² , Jon Ulf Hansen ³ , Joanne Hewitt ⁴ , Edgars Liepins ⁵ , Pawel Donets ⁵ , Laura Espina ⁶ , Alistair J M Farley ² , Kirill Shubin ⁵ , Gonzalo Gomez Campillos ² , Paula Kiuru ⁷ , Shifali Shishodia ² ⁸ , Daniel Krahn ² , Robert K Leśniak ² , Juliane Schmidt Adrian ² , Karina Calvopiña ² , María-Carmen Turrientes ⁹ , Madeline E Kavanagh ² ¹⁰ , Dmitrijs Lubriks ⁵ , Philip Hinchliffe ¹¹ , Gareth W Langley ² ¹² , Ali F Aboklaish ⁶ , Anders Eneroth ¹³ , Maria Backlund ¹³ , Andrei G Baran ⁵ , Elisabet I Nielsen ¹⁴ , Michael Speake ⁴ ¹⁵ , Janis Kuka ⁵ , John Robinson ⁴ ¹⁵ , Solveiga Grinberga ⁵ , Lindsay Robinson ⁴ ¹⁵ , Michael A McDonough ² , Anna M Rydzik ² ¹⁶ , Thomas M Leissing ² , Juan Carlos Jimenez-Castellanos ¹¹ ¹⁷ , Matthew B Avison ¹¹ , Solange Da Silva Pinto ² , Andrew D Pannifer ⁴ , Marina Martjuga ⁵ , Emma Widlake ⁶ , Martins Priede ⁵ , Iva Hopkins Navratilova ⁴ , Marek Gniadkowski ¹⁸ , Anna Karin Belfrage ¹⁹ , Peter Brandt ¹⁹ ²⁰ , Jari Yli-Kauhaluoma ⁷ , Eric Bacque ²¹ , Malcolm G P Page ²² , Fredrik Björkling ²³ , Jonathan M Tyrrell ⁶ ¹¹ , James Spencer ¹¹ , Pauline A Lang ² , Pawel Baranczewski ²⁴ , Rafael Cantón ⁹ , Stuart P McElroy ⁴ ¹⁵ , Philip S Jones ⁴ ¹⁵ , Fernando Baquero ⁹ , Edgars Suna ⁵ , Angus Morrison ⁴ ¹⁵ , Timothy R Walsh ⁶ , Christopher J Schofield ²⁵

Affiliations

1. Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK. [email protected].
2. Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK.
3. Statens Serum Institut, Copenhagen, Denmark.
4. University of Dundee, European Screening Centre, BioCity Scotland, Newhouse, UK.
5. Latvian Institute of Organic Synthesis, Riga, Latvia.
6. Department of Medical Microbiology, Institute of infection & Immunity, Cardiff University, Cardiff, UK.
7. Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
8. Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.
9. Department of Microbiology, Ramón y Cajal University Hospital and Ramón y Cajal Institute for Health Research (IRYCIS), Madrid, Spain.
10. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
11. School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
12. Charles River Laboratories, Saffron Walden, UK.
13. Department of Pharmacy, Uppsala Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala University, Uppsala, Sweden.
14. Department of Pharmacy, Uppsala University, Uppsala, Sweden.
15. BioAscent Discovery Ltd, Newhouse, UK.
16. Research and Early Development, Respiratory & Immunology, AstraZeneca, Mölndal, Sweden.
17. Chemical Biology of Antibiotics, Centre for Infection & Immunity (CIIL), Pasteur Institute, INSERM U1019 - CNRS UMR 9017, Lille, France.
18. Department of Molecular Microbiology, National Medicines Institute, Warsaw, Poland.
19. Department of Medicinal Chemistry, Drug Design and Discovery, Uppsala University, Uppsala, Sweden.
20. Beactica Therapeutics AB, Uppsala, Sweden.
21. Evotec Infectious Diseases Lyon, Marcy l'Etoile, France.
22. Jacobs University Bremen gGmbH, Bremen, Germany.
23. Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
24. Department of Pharmacy, SciLifeLab Drug Discovery and Development Platform, ADME of Therapeutics Facility, Uppsala University, Uppsala, Sweden.
25. Department of Chemistry, Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, UK. [email protected].

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.