Global emergence of Gram-negative bacteria carrying the plasmid-borne resistance genes, bla_MBL and mcr, raises a significant challenge to the treatment of life-threatening infections by the antibiotics, carbapenem and colistin (COL). Here, we identify an antirheumatic drug, auranofin (AUR) as a dual inhibitor of metallo-β-lactamases (MBLs) and mobilized colistin resistance (MCRs), two resistance enzymes that have distinct structures and substrates. We demonstrate that AUR irreversibly abrogates both enzyme activity via the displacement of Zn(II) cofactors from their active sites. We further show that AUR synergizes with antibiotics on killing a broad spectrum of carbapenem and/or COL resistant bacterial strains, and slows down the development of β-lactam and COL resistance. Combination of AUR and COL rescues all mice infected by Escherichia coli co-expressing MCR-1 and New Delhi metallo-β-lactamase 5 (NDM-5). Our findings provide potential therapeutic strategy to combine AUR with antibiotics for combating superbugs co-producing MBLs and MCRs.

携带质粒传播的抗性基因bla _MBL和mcr的革兰氏阴性细菌在全球范围内出现，对抗生素，碳青霉烯和粘菌素（COL）威胁生命的感染的治疗提出了重大挑战。在这里，我们确定了一种抗风湿药金诺芬（AUR）作为金属β-内酰胺酶（MBL）和动员的大肠菌素抗性（MCR）的双重抑制剂，这两种抗性酶具有不同的结构和底物。我们证明，AUR通过从其活性位点置换Zn（II）辅助因子，不可逆地消除了这两种酶的活性。我们进一步表明，AUR与抗生素协同作用，可杀死广谱的碳青霉烯和/或COL抗药性菌株，并减慢β-内酰胺和COL抗药性的发展。AUR和COL的组合可以挽救所有被大肠杆菌感染的小鼠共表达MCR-1和新德里金属β-内酰胺酶5（NDM-5）。我们的发现提供了潜在的治疗策略，可将AUR与抗生素结合使用，以对抗共同产生MBL和MCR的超级细菌。