Novel Piperazine Arylideneimidazolones Inhibit the AcrAB-TolC Pump in Escherichia coli and Simultaneously Act as Fluorescent Membrane Probes in a Combined Real-Time Influx and Efflux Assay

Antimicrobial Agents and Chemotherapy
Jürgen A BohnertKatarzyna Kieć-Kononowicz

Abstract

In this study, we tested five compounds belonging to a novel series of piperazine arylideneimidazolones for the ability to inhibit the AcrAB-TolC efflux pump. The biphenylmethylene derivative (BM-19) and the fluorenylmethylene derivative (BM-38) were found to possess the strongest efflux pump inhibitor (EPI) activities in the AcrAB-TolC-overproducingEscherichia colistrain 3-AG100, whereas BM-9, BM-27, and BM-36 had no activity at concentrations of up to 50 μM in a Nile red efflux assay. MIC microdilution assays demonstrated that BM-19 at 1/4 MIC (intrinsic MIC, 200 μM) was able to reduce the MICs of levofloxacin, oxacillin, linezolid, and clarithromycin 8-fold. BM-38 at 1/4 MIC (intrinsic MIC, 100 μM) was able to reduce only the MICs of oxacillin and linezolid (2-fold). Both compounds markedly reduced the MIC of rifampin (BM-19, 32-fold; and BM-38, 4-fold), which is suggestive of permeabilization of the outer membrane as an additional mechanism of action. Nitrocefin hydrolysis assays demonstrated that in addition to their EPI activity, both compounds were in fact weak permeabilizers of the outer membrane. Moreover, it was found that BM-19, BM-27, BM-36, and BM-38 acted as near-infrared-emitting fluorescent membrane probes, whic...Continue Reading

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Citations

Mar 16, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Gabriella SpenglerLeonard Amaral
Sep 11, 2018·Expert Opinion on Drug Discovery·Paula BlancoManuel Alcalde-Rico
Aug 22, 2018·Infection and Immunity·Yuehui ZhuJames M Fleckenstein
Jan 30, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Aneta KaczorJadwiga Handzlik
Feb 13, 2019·FEMS Microbiology Letters·Dahyun Hwang, Young-Hee Lim
May 15, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Aneta KaczorJadwiga Handzlik
Dec 15, 2019·Bioorganic & Medicinal Chemistry Letters·Bec J RoldanLarryn W Peterson
Feb 21, 2021·Scientific Reports·Erika BoulantJean Michel Bolla
May 4, 2021·Current Opinion in Microbiology·Helen I ZgurskayaPaolo Ruggerone

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