title: The silver cation (Ag+): antistaphylococcal activity, mode of action and resistance studies.
abstract: OBJECTIVE
  To examine several poorly understood or contentious aspects of the antibacterial activity of silver (Ag(+)), including its cidality, mode of action, the prevalence of resistance amongst clinical staphylococcal isolates and the propensity for Staphylococcus aureus to develop Ag(+) resistance.
  
  
  METHODS
  The effects of Ag(+) on the viability, macromolecular synthesis and membrane integrity of S. aureus SH1000 were assessed using established methodology. Silver nitrate MICs were determined for a collection of staphylococcal isolates (n = 1006) collected from hospitals across Europe and Canada between 1997 and 2010. S. aureus biofilms were grown using the Calgary Biofilm Device. To examine the in vitro development of staphylococcal resistance to Ag(+), bacteria were subjected to continuous subculture in the presence of sub-MIC concentrations of Ag(+).
  
  
  RESULTS
  Silver was bactericidal against S. aureus in buffered solution, but bacteriostatic in growth medium, and was unable to eradicate staphylococcal biofilms in vitro. Challenge of S. aureus with Ag(+) caused rapid loss of membrane integrity and inhibition of the major macromolecular synthetic pathways. All clinical staphylococcal isolates were susceptible to ≤ 16 mg/L silver nitrate and prolonged exposure (42 days) to Ag(+) in vitro failed to select resistant mutants.
  
  
  CONCLUSIONS
  The rapid and extensive loss of membrane integrity observed upon challenge with Ag(+) suggests that the antibacterial activity results directly from damage to the bacterial membrane. The universal susceptibility of staphylococci to Ag(+), and failure to select for resistance to Ag(+), suggest that silver compounds remain a viable option for the prevention and treatment of topical staphylococcal infections.
authors.affiliation: Antimicrobial Research Centre and School of Molecular and Cellular Biology,  University of Leeds, Leeds LS2 9JT,  UK.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Randall
authors.forename: Linda B
authors.initials: LB
authors.lastname: Oyama
authors.forename: Julieanne M
authors.initials: JM
authors.lastname: Bostock
authors.forename: Ian
authors.initials: I
authors.lastname: Chopra
authors.forename: Alex J
authors.initials: AJ
authors.lastname: O'Neill
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000891:Anti-Infective Agents, Local / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D003470:Culture Media; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D012835:Silver Nitrate / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000900:Anti-Bacterial Agents; D000891:Anti-Infective Agents, Local; D003470:Culture Media; D012835:Silver Nitrate