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

Colistin is a crucial drug for treating multidrug-resistant (MDR) Escherichia coli infections. The emergence and bacterial transmission of the colistin-resistant gene mcr-1 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 mcr-1-positive MDR E. coli 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 Galleria mellonella and mouse peritonitis infection models, NTX improved the therapeutic effect of colistin against E. coli infections. In conclusion, NTX is identified as a promising colistin adjuvant for the treatment of colistin-resistant bacterial infections.