Resensitizing carbapenem- and colistin-resistant bacteria to antibiotics using auranofin

Global emergence of Gram-negative bacteria carrying plasmid-borne resistance genes, including blaMBL and mcr, challenges the treatment of life-threatening infections with carbapenems and colistin. This study identifies the antirheumatic drug auranofin (AUR) as a dual inhibitor of metallo-β-lactamases (MBLs) and mobilized colistin resistance enzymes (MCRs), which have distinct structures and substrates. AUR irreversibly abrogates both enzyme activities by displacing Zn(II) cofactors from their active sites. AUR synergizes with antibiotics to kill a broad spectrum of carbapenem- and/or colistin-resistant bacteria and slows the development of β-lactam and colistin resistance. Combination of AUR and colistin rescues all mice infected by Escherichia coli co-expressing MCR-1 and NDM-5. These findings support combining AUR with antibiotics to combat pathogens co-producing MBLs and MCRs.