**5. Conclusions**

In this review we listed numerous cases in which silver ions were reported to exhibit efficient antibacterial activity. We also reviewed the emerging trend of using silver ions as adjuvants for potentiating antibiotic toxicity. It is compelling that after so many years, the actual reason silver kills bacteria is still eluding us. In fact, it is likely that silver ions act upon multiple different targets, from macromolecules to free amino-acid like cysteine or small molecule such as glutathion, and therefore renders it difficult, if not impossible, to trace the actual cause of death of a silver treated bacterium. Nevertheless, some pressing issues remain: Is silver destabilising protein components of respiratory chains? Does silver have any deleterious (mutagenic?) effect on genome integrity? What is the actual structural state of a silver-destabilised membrane? What is the link, if any, between silver and ROS production?

There is little doubt that new efforts should be dedicated towards the understanding of the action of silver such that this very ancient antibacterial metal can be further exploited within the context of the multiple antibiotic resistance crisis. Interest for such a potential path is reinforced by the fact that pharmacological, toxicological and pharmacokinetic modelling studies indicated that human health risks associated with silver exposure were low [27,28]. From a broader perspective, recently, we advocated the need to take into account iron in its influence on antibiotic sensitivity [29]. It is known that most metals can have antibacterial activities at high concentration, such as bismuth, cobalt, copper and cadmium, to cite a few [15,30–32]. Aiming at characterising and further exploiting their biocide activity might be a rewarding goal.

**Author Contributions:** Conceptualization, F.B. and B.E.; Investigation, L.A. and B.E.; Writing-Original Draft Preparation, F.B. and B.E.; Writing-Review & Editing, F.B. and B.E.; Funding Acquisition, F.B., L.A. and B.E.

**Funding:** This research was funded by Joint Programming Initiative on Antimicrobial Resistance (JPIAMR)/Agence Nationale de la Recherche (ANR) gran<sup>t</sup> number ANR-15-JAMR-0003-02 Combinatorial, Fondation pour la Recherche Médicale (FRM), CNRS and Aix Marseille Université.

**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.
