Principe, Luigi and Vecchio, Graziella and Sheehan, Gerard and Kavanagh, Kevin and Morroni, Gianluca and Viaggi, Valentina and di Masi, Alessandra and Giacobbe, Daniele Roberto and Luzzaro, Francesco and Luzzati, Roberto and Di Bella, Stefano (2020) Zinc Chelators as Carbapenem Adjuvants for Metallo-β-Lactamase-Producing Bacteria: In Vitro and In Vivo Evaluation. Microbial Drug Resistance, 26 (10). pp. 1133-1143. ISSN 1076-6294

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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.

Item Type:	Article
Keywords:	beta-lactamases; chelating agents; zinc; Galleria mellonella; meropenem; mortality;
Academic Unit:	Faculty of Science and Engineering > Biology Faculty of Science and Engineering > Research Institutes > Human Health Institute
Item ID:	16144
Identification Number:	https://doi.org/10.1089/mdr.2020.0037
Depositing User:	Dr. Kevin Kavanagh
Date Deposited:	20 Jun 2022 10:53
Journal or Publication Title:	Microbial Drug Resistance
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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