title: Silver potentiates aminoglycoside toxicity by enhancing their uptake.
abstract: The predicted shortage in new antibiotics has prompted research for chemicals that could act as adjuvant and enhance efficacy of available antibiotics. In this study, we tested the effects of combining metals with aminoglycosides on Escherichia coli survival. The best synergizing combination resulted from mixing aminoglycosides with silver. Using genetic and aminoglycoside uptake assays, we showed that silver potentiates aminoglycoside action in by-passing the PMF-dependent step, but depended upon protein translation. We showed that oxidative stress or Fe-S cluster destabilization were not mandatory factors for silver potentiating action. Last, we showed that silver allows aminoglycosides to kill an E. coli gentamicin resistant mutant as well as the highly recalcitrant anaerobic pathogen Clostridium difficile. Overall this study delineates the molecular basis of silver's potentiating action on aminoglycoside toxicity and shows that use of metals might offer solutions for battling against increased bacterial resistance to antibiotics.
authors.affiliation: Laboratoire de Chimie Bactérienne, Institut de Microbiologie de la Méditerranée, Aix-Marseille Université, CNRS, UMR 7283, 31 Chemin Joseph Aiguier, 13009, Marseille, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Herisse
authors.affiliation: Laboratoire de Chimie Bactérienne, Institut de Microbiologie de la Méditerranée, Aix-Marseille Université, CNRS, UMR 7283, 31 Chemin Joseph Aiguier, 13009, Marseille, France.
authors.forename: Yohann
authors.initials: Y
authors.lastname: Duverger
authors.affiliation: Institut Pasteur 25-28, rue du Docteur Roux, Laboratoire Pathogenèse des Bactéries Anaérobies, 75724, Paris, Cedex 15, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Martin-Verstraete
authors.affiliation: Laboratoire de Chimie Bactérienne, Institut de Microbiologie de la Méditerranée, Aix-Marseille Université, CNRS, UMR 7283, 31 Chemin Joseph Aiguier, 13009, Marseille, France.
authors.forename: Frédéric
authors.identifier: 0000-0003-3458-2574
authors.initials: F
authors.lastname: Barras
authors.affiliation: Laboratoire de Chimie Bactérienne, Institut de Microbiologie de la Méditerranée, Aix-Marseille Université, CNRS, UMR 7283, 31 Chemin Joseph Aiguier, 13009, Marseille, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ezraty
mesh_terms: D000617:Aminoglycosides / Q000378:metabolism* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001424:Bacterial Infections / Q000188:drug therapy; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D005839:Gentamicins / Q000493:pharmacokinetics; D008826:Microbial Sensitivity Tests / Q000379:methods; D012834:Silver / Q000378:metabolism* / Q000627:therapeutic use*
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D005839:Gentamicins; D012834:Silver