Fig. 10: Model for the mechanism of synergy between kaempferol and colistin.

The blue section of the diagram (left) describes cellular processes when bacteria are exposed only to sub-MIC amounts of colistin. In this case, ROS production can be reversed as Fenton’s reaction can take place, while the superoxide generated from the action of colistin can be converted to less toxic products by SodB. A normal expression of iron-dependant and iron-storage proteins, as well as siderophore biosynthesis and transport genes is depicted. The red section of the diagram (right) describes the dysregulation of iron homeostasis caused by the action of kaempferol that chelates Fe³⁺, including downregulation of genes encoding iron-dependent and iron-storage proteins and upregulation of siderophore biosynthesis and transport genes. Dysregulation of iron homeostasis, in turn, results in accumulation of ROS due to the action of colistin and inhibition of the Fenton reaction (thick red borders). In addition, imbalance in the intracellular iron content makes less iron available for SodB, and therefore inhibits the superoxide de-toxification process. Eventually this accumulation of ROS leads to extensive damage to lipids, proteins, nucleic acids and, ultimately, cell death. The figure was created using BioRender.com.