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


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.


CONCLUSIONS
Phosphorus ylides might be valuable EPI compounds to reverse efflux related MDR in bacteria.
Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
Annamária
A
Kincses
Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
Ágnes Míra
ÁM
Szabó
Faculty of Pharmaceutical Sciences, Matsuyama University, Matsuyamas, Japan.
Ryosuke
R
Saijo
Faculty of Pharmaceutical Sciences, Matsuyama University, Matsuyamas, Japan.
Genki
G
Watanabe
Faculty of Pharmaceutical Sciences, Matsuyama University, Matsuyamas, Japan.
Masami
M
Kawase
Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
Joseph
J
Molnár
Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary spengler.gabriella@med.u-szeged.hu.
Gabriella
G
Spengler
D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects* / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005470:Fluorometry / Q000379:methods; D017353:Gene Deletion; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry / Q000494:pharmacology*; D008074:Lipoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053038:Quorum Sensing / Q000187:drug effects / Q000235:genetics
D001425:Bacterial Outer Membrane Proteins; D029968:Escherichia coli Proteins; D006845:Hydrocarbons, Fluorinated; D008074:Lipoproteins; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C083497:AcrA protein, E coli; C083496:AcrB protein, E coli; C073126:tolC protein, E coli
Phosphorus ylides; bacterial AcrAB-TolC; efflux pump; multidrug resistance; quorum sensing