Re-sensitization of mcr carrying multidrug resistant bacteria to colistin by silver.

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.