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

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 was 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) were prepared. Killing kinetics and live/dead assays confirmed the antibacterial activity of Lipo-cc against colistin-resistant bacteria, which was more potent than that of the free curcumin and colistin combination. Mechanistical studies revealed that Lipo-cc restored the affinity of colistin for the bacterial membrane and improved the uptake of curcumin, which led to reduced efflux pump activity, achieving a synergistic effect of colistin and curcumin. At the effective antibacterial dose, Lipo-cc did not exhibit any toxicity. The therapeutic efficacy of Lipo-cc was further demonstrated in an intestinal bacterial infection model induced with colistin-resistant Escherichia coli. Lipo-cc reduced the bacterial burden with over 6-log reduction and alleviated inflammation caused by infection. Importantly, unlike colistin, Lipo-cc did 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. This article is protected by copyright. All rights reserved.