The potency of gepotidacin and zoliflodacin in fluoroquinolone-resistant Escherichia coli upon tolC inactivation.

Inactivating tolC in multidrug-resistant Escherichia coli with differing sequence types and quinolone resistance-determining mutations reveals remarkably potentiated activity of the first-in-class topoisomerase inhibitors gepotidacin and zoliflodacin. Differences between both structurally unrelated compounds in comparison to fluoroquinolones regarding the selectivity of E. coli RND-type transporters, of efflux inhibitors, and of AcrB porter domain mutations were demonstrated. The findings should reinforce efforts to develop efflux bypassing drugs and provide AcrB targets with critical relevance for this purpose.