Nitroxoline as an antimicrobial synergist reverses colistin resistance in multidrug-resistant Escherichia coli

Colistin is a crucial drug for treating multidrug-resistant (MDR) <i>Escherichia coli</i> infections. The emergence and bacterial transmission of the colistin-resistant gene <i>mcr-1</i> have substantially diminished its therapeutic efficacy. The development of colistin enhancers represents an effective strategy to counteract this resistance. This study demonstrates that the FDA-approved drug nitroxoline (NTX) synergistically enhances the antibacterial activity of colistin against <i>mcr-1</i>-positive MDR <i>E. coli</i> and effectively suppresses the development of colistin resistance. Functional assays and transcriptomic profiling demonstrate that NTX targets MCR-1, thereby potentiating the membrane-disruptive activity of colistin. Moreover, the combined administration of NTX and colistin perturbs bacterial metabolic pathways, provokes oxidative damage, and accelerates bacterial death. Furthermore, in both the <i>Galleria mellonella</i> and mouse peritonitis infection models, NTX improved the therapeutic effect of colistin against <i>E. coli</i> infections. In conclusion, NTX is identified as a promising colistin adjuvant for the treatment of colistin-resistant bacterial infections.