Fluorinated Beta-diketo Phosphorus Ylides Are Novel Efflux Pump Inhibitors in Bacteria

Abstract

Background: One of the most important resistance mechanisms in bacteria is the increased expression of multidrug efflux pumps. To combat efflux-related resistance, the development of new efflux pump inhibitors is essential.

Materials and methods: Ten phosphorus ylides were compared based on their MDR-reverting activity in multidrug efflux pump system consisting of the subunits acridine-resistance proteins A and B (AcrA and AcrB) and the multidrug efflux pump outer membrane factor TolC (TolC) of Escherichia coli K-12 AG100 strain and its AcrAB-TolC-deleted strain. Efflux inhibition was assessed by real-time fluorimetry and the inhibition of quorum sensing (QS) was also investigated. The relative gene expression of efflux QS genes was determined by real-time reverse transcriptase quantitative polymerase chain reaction.

Results: The most potent derivative was Ph₃P=C(COC₂F₅)CHO and its effect was more pronounced on the AcrAB-TolC-expressing E. coli strain, furthermore the most active compounds, Ph₃P=C(COCF₃)OMe, Ph₃P=C(COC₂F₅)CHO and Ph₃P=C(COCF₃)COMe, reduced the expression of efflux pump and QS genes.

Conclusion: Phosphorus ylides might be valuable EPI compounds to reverse efflux related MDR in bacteria.

Keywords: Phosphorus ylides; bacterial AcrAB-TolC; efflux pump; multidrug resistance; quorum sensing.