Liposomes Co‐Delivering Curcumin and Colistin to Overcome Colistin Resistance in Bacterial Infections

Abstract Antibiotic colistin is the last line of defense against multidrug‐resistant (MDR) Gram‐negative bacterial infections. Emergence of colistin resistance in microbes is a critical challenge. Herein, curcumin is discovered, for the first time, to reverse the resistance phenotype of colistin‐resistant bacteria via a checkerboard assay. For the co‐delivery of curcumin and colistin, negatively charged poly(ethylene glycol)‐functionalized liposomes encapsulating both drugs (Lipo‐cc) are prepared. Killing kinetics and live/dead assays confirm the antibacterial activity of Lipo‐cc against colistin‐resistant bacteria, which is more potent than that of the free curcumin and colistin combination. Mechanistical studies reveal that Lipo‐cc restores the affinity of colistin for the bacterial membrane and improves the uptake of curcumin, which leads to reduced efflux pump activity, achieving a synergistic effect of colistin and curcumin. At the effective antibacterial dose, Lipo‐cc does not exhibit any toxicity. The therapeutic efficacy of Lipo‐cc is further demonstrated in an intestinal bacterial infection model induced with colistin‐resistant Escherichia coli . Lipo‐cc reduces the bacterial burden with over 6‐log reduction and alleviated inflammation caused by infection. Importantly, unlike colistin, Lipo‐cc does not affect the homeostasis of the intestinal flora. Taken together, Lipo‐cc successfully overcame colistin resistance, indicating its potential for the treatment of colistin‐resistant bacterial infections.