The silver cation (Ag+): antibacterial mode of action and mechanisms of resistance

The increasing prevalence of infections attributed to antibiotic-resistant bacteria has prompted renewed interest in exploiting the antibacterial properties of Ag+ to treat such infections. However, the antibacterial mode of action (MOA) and bactericidal activity of Ag+ are poorly understood, and there are concerns that the prolific and unrestricted use of Ag+ in consumer products will select bacterial Ag+ resistance, thus limiting the clinical utility of Ag+. Ag+ resistance already exists, although aspects of the molecular basis of Ag+ resistance, and the current prevalence of Ag+-resistant pathogens are unclear. This thesis sought to address these issues.
Ag+ was found to be bacteriostatic in culture media and bactericidal in buffer, and was unable to eradicate Staphylococcus aureus biofilms in vitro. MOA studies indicated that the primary antibacterial target of Ag+ is the cell membrane. Evidence was obtained suggesting that Ag+ does not interfere with the phospholipid component of the membrane, but instead probably damages integral membrane proteins to produce an antibacterial effect.
A survey of hospital staphylococcal isolates (n=1006) found universal susceptibility to Ag+, and Ag+ resistance could not be selected in S. aureus and several other pathogens in vitro. However, in Escherichia coli, high-level Ag+ resistance arose rapidly and was not associated with a fitness cost likely to prevent its emergence in the clinical setting. Ag+-resistant strains contained mutations in genes regulating expression of an Ag+ efflux mechanism and outer membrane porins. A detailed characterisation of a known Ag+-resistance determinant (the sil operon), was also conducted to provide further insights into the mechanism of Ag+ resistance conferred by this determinant.
Collectively, these studies provide further insights into the MOA of Ag+ and the mechanisms of Ag+ resistance, which could potentially be applied to optimising the future uses of Ag+ as an antibacterial agent.