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Small Molecule Carboxylates Inhibit Metallo-β-lactamases and Resensitize Carbapenem-Resistant Bacteria to Meropenem

Authors
  • Tehrani, Kamaleddin H. M. E.1
  • Brüchle, Nora C.1
  • Wade, Nicola1
  • Mashayekhi, Vida2
  • Pesce, Diego3, 4
  • van Haren, Matthijs J.1
  • Martin, Nathaniel I.1
  • 1 Leiden University, The Netherlands
  • 2 Utrecht University, The Netherlands
  • 3 Wageningen University and Research, The Netherlands
  • 4 University of Zurich, Switzerland , (Switzerland)
Type
Published Article
Journal
ACS Infectious Diseases
Publisher
American Chemical Society
Publication Date
Mar 31, 2020
Volume
6
Issue
6
Pages
1366–1371
Identifiers
DOI: 10.1021/acsinfecdis.9b00459
PMID: 32227874
PMCID: PMC7296533
Source
PubMed Central
Keywords
License
Unknown

Abstract

In the search for new inhibitors of bacterial metallo-β-lactamases (MBLs), a series of commonly used small molecule carboxylic acid derivatives were evaluated for their ability to inhibit New Delhi metallo-β-lactamase (NDM)-, Verona integron-encoded metallo-β-lactamase (VIM)-, and imipenemase (IMP)-type enzymes. Nitrilotriacetic acid ( 3 ) and N -(phosphonomethyl)iminodiacetic acid ( 5 ) showed promising activity especially against NDM-1 and VIM-2 with IC50 values in the low-to-sub μM range. Binding assays using isothermal titration calorimetry reveal that 3 and 5 bind zinc with high affinity with dissociation constant ( K d) values of 121 and 56 nM, respectively. The in vitro biological activity of 3 and 5 against E. coli expressing NDM-1 was evaluated in checkerboard format, demonstrating a strong synergistic relationship for both compounds when combined with Meropenem. Compounds 3 and 5 were then tested against 35 pathogenic strains expressing MBLs of the NDM, VIM, or IMP classes. Notably, when combined with Meropenem, compounds 3 and 5 were found to lower the minimum inhibitory concentration (MIC) of Meropenem up to 128-fold against strains producing NDM- and VIM-type enzymes.

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