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Colistin is considered the last-line antimicrobial for the treatment of multidrug-resistant gram-negative bacterial infections. The emergence and spread of superbugs carrying the mobile colistin resistance gene ( mcr ) have become the most serious and urgent threat to healthcare. Here, we discover that silver (Ag + ), including silver nanoparticles, could restore colistin efficacy against mcr -positive bacteria. We show that Ag + inhibits the activity of the MCR-1 enzyme via substitution of Zn 2+ in the active site. Unexpectedly, a tetra-silver center was found in the active-site pocket of MCR-1 as revealed by the X-ray structure of the Ag-bound MCR-1, resulting in the prevention of substrate binding. Moreover, Ag + effectively slows down the development of higher-level resistance and reduces mutation frequency. Importantly, the combined use of Ag + at a low concentration with colistin could relieve dermonecrotic lesions and reduce the bacterial load of mice infected with mcr -1–carrying pathogens. This study depicts a mechanism of Ag + inhibition of MCR enzymes and demonstrates the potentials of Ag + as broad-spectrum inhibitors for the treatment of mcr -positive bacterial infection in combination with colistin.

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.

Affiliation 1 incorrectly read "Department of Chemistry, The University of Hong Kong, Hong Kong S.A.R., People's Republic of China". This has now been corrected to "Department of Chemistry, State Key Laboratory of Synthetic Chemistry, CAS-HKU Joint Laboratory of Metallomics on Health and Environment, The University of Hong Kong, Hong Kong S.A.R., People's Republic of China". in both the PDF and HTML versions of the Article. [Extracted from the article]