Re-sensitization of <i>mcr</i> carrying multidrug resistant bacteria to colistin by silver

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 (<i>mcr</i>) have become the most serious and urgent threat to healthcare. Here, we discover that silver (Ag⁺), including silver nanoparticles, could restore colistin efficacy against <i>mcr</i>-positive bacteria. We show that Ag⁺ inhibits the activity of the MCR-1 enzyme via substitution of Zn²⁺ 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 <i>mcr</i>-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 <i>mcr</i>-positive bacterial infection in combination with colistin.