A declining pipeline of clinically useful
antibiotics has made it imperative to develop more effective antimicrobial
therapies, particularly against difficult-to-treat Gram-negative pathogens.
Silver has been used as an antimicrobial since antiquity, yet its mechanism of action remains unclear. We show that
silver disrupts multiple bacterial cellular processes, including
disulfide bond formation, metabolism, and
iron homeostasis. These changes lead to increased production of
reactive oxygen species and increased membrane permeability of Gram-negative bacteria that can potentiate the activity of a broad range of
antibiotics against Gram-negative bacteria in different metabolic states, as well as restore
antibiotic susceptibility to a resistant bacterial strain. We show both in vitro and in a mouse model of
urinary tract infection that the ability of
silver to induce oxidative stress can be harnessed to potentiate
antibiotic activity. Additionally, we demonstrate in vitro and in two different mouse models of
peritonitis that
silver sensitizes Gram-negative bacteria to the Gram-positive-specific
antibiotic vancomycin, thereby expanding the antibacterial spectrum of this
drug. Finally, we used
silver and
antibiotic combinations in vitro to eradicate bacterial persister cells, and show both in vitro and in a mouse biofilm
infection model that
silver can enhance antibacterial action against bacteria that produce biofilms. This work shows that
silver can be used to enhance the action of existing
antibiotics against Gram-negative bacteria, thus strengthening the
antibiotic arsenal for fighting
bacterial infections.