Silver Enhances Antibiotic Activity Against Gram-Negative Bacteria

Silver enhances the activity of a wide range of antibiotics and broadens the spectrum of vancomycin, rendering it effective against Gram-negative bacteria. A Silver Spoon Makes the Medicine Go Down There is a growing need to enhance our antibacterial arsenal given the rising incidence of antibiotic resistance and the emergence of new virulent pathogens. Drug-resistant, difficult-to-treat Gram-negative bacterial infections have forced clinicians to revisit the use of older antimicrobials that have previously been discarded. Such is the case of silver, an intriguing compound that, despite its long-standing history as an antimicrobial (since 400 B.C.), has an unclear bactericidal mode of action. In their new study, Morones-Ramirez and his colleagues use a systems-based approach to show that silver disrupts multiple bacterial cellular processes, leading to increased production of reactive oxygen species and increased membrane permeability of Gram-negative bacteria. The authors harnessed these effects to potentiate the activity of a broad range of antibiotics against Gram-negative bacteria in different metabolic states, as well as to restore antibiotic susceptibility to resistant bacterial strains. They show both in vitro and in vivo that (i) silver’s ability to induce oxidative stress can be harnessed to potentiate antibiotic activity; (ii) silver sensitizes Gram-negative bacteria to the Gram-positive–specific antibiotic vancomycin, thereby expanding the antibacterial spectrum of this drug; and (iii) silver enhances antibiotic activity against bacterial persister cells and biofilms. This new study provides a way to enhance the activity of existing antimicrobials and goes some way toward enlarging the dwindling armamentarium of drugs to fight bacterial diseases. 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.