Abstract
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.