Bacterial Silver Resistance Gained by Cooperative Interspecies 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 (Ag⁰), 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 Ag⁰ 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 Ag⁰ 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.