Bacterial Silver Resistance Gained by Cooperative lnterspecies Redox Behavior

Silver has emerged as an important therapeutic option for wound infections in recent years due to its broad-spectrum antimicrobial activity. The silver cation (Ag+), but not the bulk metal (Ag degrees), is highly toxic for most microorganisms, although resistance due to genetic modification or horizontal gene transfer does occur. Pseudomonas aeruginosa, however, achieves silver resistance by producing the redox-active metabolite pyocyanin that reduces Ag+ to nontoxic Ag degrees. Pyocyanin also possesses broad-spectrum antimicrobial activity. Many microbial species reduce pyocyanin, which reduces molecular oxygen to antimicrobial hydrogen peroxide. In this study, it was hypothesized that both Ag+ and oxygen would act as competing terminal electron acceptors for pyocyanin, thus acting as a universal microbial protectant from Ag+ while avoiding hydrogen peroxide formation. Escherichia coli and Staphylococcus aureus efficiently reduced pyocyanin and generated hydrogen peroxide, while Ag+ markedly reduced the amount of hydrogen peroxide produced. Although unable to reduce directly Ag+ to Ag degrees on their own, E. coli and S. aureus did so when pyocyanin was present, resulting in increased survival when exposed to Ag+. Coincubation experiments with either E. coli or S. aureus with P. aeruginosa demonstrated increased survival for those species to Ag+, but only if pyocyanin was present. These data demonstrate that microorganisms that display no intrinsic silver resistance may survive and proliferate under potentially toxic conditions, provided their environment contains a suitable redox-active metabolite-producing bacterium. Chronic wounds are often polymicrobial in nature, with pyocyanin-producing P. aeruginosa bacteria frequently being present; therefore, redox-based silver resistance may compromise treatment efforts.