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Polypyridine ligands as potential metallo-β-lactamase inhibitors.
- Source :
-
Journal of inorganic biochemistry [J Inorg Biochem] 2021 Feb; Vol. 215, pp. 111315. Date of Electronic Publication: 2020 Nov 21. - Publication Year :
- 2021
-
Abstract
- Bacteria have developed multiple resistance mechanisms against the most used antibiotics. In particular, zinc-dependent metallo-β-lactamase producing bacteria are a growing threat, and therapeutic options are limited. Zinc chelators have recently been investigated as metallo-β-lactamase inhibitors, as they are often able to restore carbapenem susceptibility. We synthesized polypyridyl ligands, N,N'-bis(2-pyridylmethyl)-ethylenediamine, N,N,N'-tris(2-pyridylmethyl)-ethylenediamine, N,N'-bis(2-pyridylmethyl)-ethylenediamine-N-acetic acid (N,N,N'-tris(2-pyridylmethyl)-ethylenediamine-N'-acetic acid, which can form zinc(II) complexes. We tested their ability to restore the antibiotic activity of meropenem against three clinical strains isolated from blood and metallo-β-lactamase producers (Klebsiella pneumoniae, Enterobacter cloacae, and Stenotrophomonas maltophilia). We functionalized N,N,N'-tris(2-pyridylmethyl)-ethylenediamine with D-alanyl-D-alanyl-D-alanine methyl ester with the aim to increase bacterial uptake. We observed synergistic activity of four polypyridyl ligands with meropenem against all tested isolates, while the combination N,N'-bis(2-pyridylmethyl)-ethylenediamine and meropenem was synergistic only against New Delhi and Verona integron-encoded metallo-β-lactamase-producing bacteria. All synergistic interactions restored the antimicrobial activity of meropenem, providing a significant decrease of minimal inhibitory concentration value (by 8- to 128-fold). We also studied toxicity of the ligands in two normal peripheral blood lymphocytes.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- Anti-Bacterial Agents pharmacology
Bacteria drug effects
Bacterial Proteins metabolism
Chelating Agents chemistry
Chelating Agents pharmacology
Drug Resistance, Bacterial
Drug Therapy, Combination
Enterobacter cloacae drug effects
Enterobacter cloacae enzymology
Gram-Negative Bacteria enzymology
Humans
Klebsiella pneumoniae drug effects
Klebsiella pneumoniae enzymology
Ligands
Meropenem pharmacology
Microbial Sensitivity Tests
Stenotrophomonas maltophilia drug effects
Stenotrophomonas maltophilia enzymology
Zinc chemistry
beta-Lactamase Inhibitors chemistry
beta-Lactamases metabolism
Gram-Negative Bacteria drug effects
Pyridines chemistry
Pyridines pharmacology
beta-Lactamase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1873-3344
- Volume :
- 215
- Database :
- MEDLINE
- Journal :
- Journal of inorganic biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33285370
- Full Text :
- https://doi.org/10.1016/j.jinorgbio.2020.111315