| Summary: | Resistance to polymyxins when treating multidrug-resistant (MDR) Gram-negative bacterial infections limit therapeutic options. Here, we report the synthesis of a nickel (Ni) doped Zinc oxide (NZO) combined with black phosphorus (BP) (NZB) nanocomposite and its synergistic action with polymyxin B (PolB) against polymyxin-resistant <i>Escherichia coli </i>harboring mobilized colistin resistance (<i>mcr-1</i>) gene. NZB and PolB combination therapy expressed a specific and strong synergy against Mcr-1 expressing <i>E. coli</i> cells. The underlying mechanism of the synergy is the charge neutralization of the <i>E. coli</i> cell surface by NZB, resulting in a more feasible incorporation of PolB to <i>E. coli</i>. The synergistic concentration of NZB with PolB was proved biocompatible. Thus, the NZB is the first biocompatible nano-adjuvant to polymyxins against polymyxin-resistant <i>E. coli</i> cells, recognizing the physical status of bacteria instead of known adjuvants targeting cellular gene products. Therefore, NZB has the potential to revive polymyxins as leading last-resort antibiotics to combat polymyxin-resistant Gram-negative bacterial infections.
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