Faropenem reacts with serine and metallo-β-lactamases to give multiple products

Anka Lucic, Philip Hinchliffe, Tika R Malla, Catherine L Tooke, Jürgen Brem, Karina Calvopiña, Christopher T Lohans, Patrick Rabe, Michael A McDonough, Timothy Armistead, Allen M Orville, James Spencer*, Christopher J Schofield*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

3 Citations (Scopus)
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Abstract

Penems have demonstrated potential as antibacterials and β-lactamase inhibitors; however, their clinical use has been limited, especially in comparison with the structurally related carbapenems. Faropenem is an orally active antibiotic with a C2 tetrahydrofuran (THF) ring, which is resistant to hydrolysis by some β-lactamases. We report studies on the reactions of faropenem with carbapenem-hydrolysing β-lactamases, focusing on the class A serine β-lactamase KPC-2 and the metallo β-lactamases (MBLs) VIM-2 (a subclass B1 MBL) and L1 (a B3 MBL). Kinetic studies show that faropenem is a substrate for all three β-lactamases, though it is less efficiently hydrolysed by KPC-2. Crystallographic analyses on faropenem-derived complexes reveal the opening of the β-lactam ring with formation of an imine with KPC-2, VIM-2, and L1. In the cases of the KPC-2 and VIM-2 structures, the THF ring is opened to give an alkene, but with L1 the THF ring remains intact. Solution state studies, employing NMR, were performed on L1, KPC-2, VIM-2, VIM-1, NDM-1, OXA-23, OXA-10, and OXA-48. The solution results reveal, in all cases, formation of imine products in which the THF ring is opened; formation of a THF ring-closed imine product was only observed with VIM-1 and VIM-2. An enamine product with a closed THF ring was also observed in all cases, at varying levels. Combined with previous reports, the results exemplify the potential for different outcomes in the reactions of penems with MBLs and SBLs and imply further structure-activity relationship studies are worthwhile to optimise the interactions of penems with β-lactamases. They also exemplify how crystal structures of β-lactamase substrate/inhibitor complexes do not always reflect reaction outcomes in solution.
Original languageEnglish
Article number113257
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume215
Early online date9 Feb 2021
DOIs
Publication statusPublished - 5 Apr 2021

Bibliographical note

Funding Information:
We thank the Medical Research Council MRC (MR/T016035/1), EPSRC, National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH, R01AI100560 to J.S.) and the Wellcome Trust for funding our research and Diamond Light Source and their beamline scientists for aiding with data collection. TRM is funded by the BBSRC (BB/M011224/1). PR thanks the Deutsche Akademie f?r Naturforscher Leopoldina, Germany, for funding a postdoctoral fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. AMO was supported in part by a Wellcome Investigator Award in Science 210734/Z/18/Z and a Royal Society Wolfson Fellowship RSWFR2182017, as well as support from the Science & Technologies Facilities Council/UK Research and Innovation.

Funding Information:
We thank the Medical Research Council MRC (MR/T016035/1), EPSRC , National Institute of Allergy and Infectious Diseases of the National Institutes of Health ( NIH , R01AI100560 to J.S.) and the Wellcome Trust for funding our research and Diamond Light Source and their beamline scientists for aiding with data collection. TRM is funded by the BBSRC (BB/M011224/1). PR thanks the Deutsche Akademie für Naturforscher Leopoldina, Germany , for funding a postdoctoral fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. AMO was supported in part by a Wellcome Investigator Award in Science 210734/Z/18/Z and a Royal Society Wolfson Fellowship RSWFR2182017 , as well as support from the Science & Technologies Facilities Council/UK Research and Innovation .

Publisher Copyright:
© 2021 The Author(s)

Keywords

  • antimicrobial resistance
  • β-lactams
  • penems
  • carbapenems
  • serine-β-lactamases
  • metallo-β-lactamases

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