Multi-target mode of action of silver against Staphylococcus aureus endows it with capability to combat antibiotic resistance

Abstract The rapid emergence of drug resistant Staphylococcus aureus ( S. aureus ) poses a serious threat to public health globally. Silver (Ag)-based antimicrobials are promising to combat antibiotic resistant S. aureus , yet their molecular targets are largely elusive. Herein, we separate and identify 38 authentic Ag + -binding proteins in S. aureus at the whole-cell scale. We then capture the molecular snapshot on the dynamic action of Ag + against S. aureus and further validate that Ag + could inhibit a key target 6-phosphogluconate dehydrogenase through binding to catalytic His185 by X-ray crystallography. Significantly, the multi-target mode of action of Ag + (and nanosilver) endows its sustainable antimicrobial efficacy, leading to enhanced efficacy of conventional antibiotics and resensitization of MRSA to antibiotics. Our study resolves the long-standing question of the molecular targets of silver in S. aureus and offers insights into the sustainable bacterial susceptibility of silver, providing a potential approach for combating antimicrobial resistance.