New Topoisomerase Inhibitors: Evaluating the Potency of Gepotidacin and Zoliflodacin in Fluoroquinolone-Resistant Escherichia coli upon tolC Inactivation and Differentiating Their Efflux Pump Substrate Nature.

Antimicrobial Agents and Chemotherapy
Sabine SchusterWinfried V Kern

Abstract

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 (resistance-nodulation-cell division)-type transporters, efflux inhibitors, and 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.

References

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Mar 28, 2012·Proceedings of the National Academy of Sciences of the United States of America·Thomas EicherKlaas M Pos
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Jul 12, 2017·International Journal of Antimicrobial Agents·Sabine SchusterWinfried V Kern
May 26, 2018·The Journal of Antimicrobial Chemotherapy·Susanne JacobssonMagnus Unemo
Feb 1, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Sabine SchusterWinfried V Kern

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