Synergy with Farnesol Rejuvenates Colistin Active against Col-R Gram-Negative Bacteria in Vitro and in Vivo

Colistin is considered the last line of treatment against infections due to multidrug-resistant (MDR) Gram-negative bacteria (GNB). However, the increasing number of colistin-resistant (Col-R) bacteria caused by the use of colistin is a great threat to public health. In this study, we proposed a strategy of combining farnesol (FAR), which has anti-inflammatory and antitumor properties, with colistin to restart colistin activity. We investigated the synergistic effect of FAR combined with colistin against Col-R GNB in vivo and in vitro. The excellent synergistic Antibacterial activity of the colistin-FAR combination was confirmed by performing the checkerboard assay, time-killing assay, and LIVE/DEAD Bacterial cell viability assay. Crystal violet staining and scanning electron microscopy results showed that colistin-FAR prevented biofilm formation and eradicated preexisting mature biofilm. Cytotoxicity assay showed that FAR at 64 μg/mL was not cytotoxic to RAW264.7 cells. In vivo Infection experiments showed that colistin-FAR increased the survival rate of infected Galleria mellonella and decreased the Bacterial load in the thigh of a mouse Infection model. Our results showed that the combination of colistin-FAR has a promising application prospect and can be an effective therapeutic option for combating Col-R GNB infections.

Gram-negative bacteria; biofilm; colistin-resistant; farnesol; synergy mechanism.