Synergy with farnesol rejuvenates colistin activity against Colistin-resistant Gram-negative bacteria in vitro and in vivo

Colistin (COL) 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 is a great threat to public health. In this study, a strategy of combining farnesol (FAR), which has anti-inflammatory and antitumor properties, with COL to restart COL activity was proposed. The synergistic effect of FAR combined with COL against COL-R GNB in vivo and in vitro were investigated. The excellent synergistic antibacterial activity of the COL–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 COL–FAR prevented biofilm formation and eradicated pre-existing mature biofilm. Cytotoxicity assay showed that FAR at 64 µg/mL was not cytotoxic to RAW264.7 cells. In vivo infection experiments showed that COL–FAR increased the survival rate of infected Galleria mellonella and decreased the bacterial load in a mouse thigh infection model. These results indicate that COL–FAR is a potentially effective therapeutic option for combating COL-R GNB infections.