Xanthohumol restores the susceptibility of Escherichia coli to colistin

Abstract The spread of colistin (CL) resistance poses a considerable threat to antibiotic stewardship. Antibiotic adjuvants in combination with antibiotics have become one of the strategies used to mitigate antibiotic resistance. We analyzed the synergistic effect of xanthohumol (XN) with CL via checkerboard tests, temporal bactericidal curve assays and resistance evolution. The synergistic mechanism was explored by testing the outer and inner cell membranes and physiological pathways. The results showed that XN had synergistic activity with CL against Gram-negative bacteria such as mucin-resistant Escherichia coli and delayed the development of CL resistance. Mechanistic studies revealed that XN enhanced the destructive effects of CL on the outer and inner membranes, inhibited intracellular adenosine triphosphate synthesis, and promoted the accumulation of reactive oxygen species. In in vivo studies, the combination of XN and CL also enhanced the therapeutic effect. These results suggest that XN is a potential adjuvant of CL against CL-resistant pathogens.