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  • Zinc Chelators as Carbapenem Adjuvants for Metallo-β-Lactamase-Producing Bacteria: In Vitro and In Vivo Evaluation.

Zinc Chelators as Carbapenem Adjuvants for Metallo-β-Lactamase-Producing Bacteria: In Vitro and In Vivo Evaluation.

Microbial drug resistance (Larchmont, N.Y.) (2020-05-05)
Luigi Principe, Graziella Vecchio, Gerard Sheehan, Kevin Kavanagh, Gianluca Morroni, Valentina Viaggi, Alessandra di Masi, Daniele Roberto Giacobbe, Francesco Luzzaro, Roberto Luzzati, Stefano Di Bella
ABSTRACT

Infections caused by metallo-β-lactamase (MBL)-producing bacteria are emerging and carry a significant impact on patients' outcome. MBL producers are spread worldwide, both in community and hospital setting, with increasingly reported epidemic clusters and the search for MBL inhibitors is an important topic for public health. MBLs are zinc-dependent enzymes whose functioning can be hampered by zinc chelators. We evaluated the potential of six zinc chelators (disulfiram, nitroxoline, 5-amino-8-hydroxyquinoline, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA], cyclam, and N,N,N',N'-tetrakis (2-pyridymethyl) ethylenediamine [TPEN]) in restoring carbapenem activity against MBL producers. Zinc chelators alone or in combination with meropenem against MBL-producing Klebsiella pneumoniae, Chryseobacterium indologenes, Elizabethkingia meningoseptica, and Stenotrophomonas maltophilia isolates were tested in vitro and in vivo (Galleria mellonella). In vitro experiments showed a synergistic activity between TPEN and meropenem toward all the strains. Nitroxoline alone retained activity against S. maltophilia, C. indologenes, and E. meningoseptica. In vivo experiments showed that TPEN or nitroxoline in combination with meropenem increased survival in larvae infected with E. meningoseptica, S. maltophilia, and K. pneumoniae. Based on our data, zinc chelators are potential carbapenem adjuvants molecules (restoring carbapenem activity) against MBL-sustained infections and could represent an interesting option for infections induced by these microorganisms.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid, ≥97.0% (CHN)
Sigma-Aldrich
N,N,N′,N′-Tetrakis(2-pyridylmethyl)ethylenediamine
Sigma-Aldrich
6-Mercaptohexanoic acid, 90%
Sigma-Aldrich
5-Aminoquinolin-8-ol