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Polypyridine ligands as potential metallo-β-lactamase inhibitors. | LitMetric

Polypyridine ligands as potential metallo-β-lactamase inhibitors.

J Inorg Biochem

Dipartimento di Scienze Chimiche, Università degli Studi di Catania, V.le A. Doria 6, 95125 Catania, Italy; Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici (CIRCMSB), Piazza Umberto I 1, 70121 Bari, Italy. Electronic address:

Published: February 2021

AI Article Synopsis

Article 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.

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Source
http://dx.doi.org/10.1016/j.jinorgbio.2020.111315DOI Listing

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