title: Inhibition of quorum sensing and efflux pump system by trifluoromethyl ketone proton pump inhibitors.
abstract: BACKGROUND
  One major microbiological problem is the widespread antibiotic resistance. There is an urgent need for new antibiotics and ways to treat multi-drug-resistant infections. Inhibition of bacterial quorum sensing (QS) systems could be an effective alternative in a smuch as they regulate a broad spectrum of cell functions, including, virulence factor production, biofilm organisation and motility. Influx and efflux bacterial systems involved in quorum sensing (QS) are known to depend on the proton motive force (PMF). Thus, a new series of 12 trifluoromethyl ketones (TFs) known to inhibit the PMF, was investigated for effects on the efflux pump of a QS responding bacterium, for its subsequent effect on the response to a QS signal and its direct inhibition of the response to a QS signal.
  
  
  METHODS
  Chromobacterium violaceum 026 (CV026) was used as the indicator strain to evaluate the QS inhibitory effect of TFs. This strain responds to the presence of short carbon chain acyl-homoserine lactones (AHLs) by the development of a purple pigment. Effect on the QS response of CV026 to externally added AHLs was evaluated. In addition, the specific activity of the TFs on the efflux pump system of the CV026 strain and a wild-type Escherichia coli strain was assessed with the aid of the automated real-time ethidium bromide method.
  
  
  RESULTS
  From the 12 compounds, 6 proved to be effective inhibitors of the QS response by CV026, as well as inhibit the efflux pumps of CV026 and Escherichia coli.
  
  
  CONCLUSIONS
  Our results show that TFs have QS inhibitory properties that are mediated through their inhibition of efflux pumps that extrude the noxious QS signal before it reaches its intended target. Because the TFs also inhibit the efflux pump of a pathogenic bacterium, the method used for the evaluation of the TFs in the current study has clinical relevance and may be exploited for the prevention of QS responses of infecting bacteria.
authors.affiliation: Institute of Medical Microbiology, University of Szeged, Szeged, Hungary.
authors.forename: Zoltán G
authors.initials: ZG
authors.lastname: Varga
authors.forename: Ana
authors.initials: A
authors.lastname: Armada
authors.forename: Pedro
authors.initials: P
authors.lastname: Cerca
authors.forename: Leonard
authors.initials: L
authors.lastname: Amaral
authors.forename: Mior A A
authors.initials: MA
authors.lastname: Mior Ahmad Subki
authors.forename: Michael A
authors.initials: MA
authors.lastname: Savka
authors.forename: Erno
authors.initials: E
authors.lastname: Szegedi
authors.forename: Masami
authors.initials: M
authors.lastname: Kawase
authors.forename: Noboru
authors.initials: N
authors.lastname: Motohashi
authors.forename: Joseph
authors.initials: J
authors.lastname: Molnár
mesh_terms: D054742:Acyl-Butyrolactones / Q000032:analysis; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D002861:Chromobacterium / Q000187:drug effects* / Q000502:physiology; D003124:Colorimetry; D004305:Dose-Response Relationship, Drug; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D048168:Escherichia coli K12 / Q000187:drug effects* / Q000502:physiology; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors; D004996:Ethidium / Q000032:analysis / Q000378:metabolism; D005456:Fluorescent Dyes / Q000032:analysis / Q000378:metabolism; D007659:Ketones / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D053038:Quorum Sensing / Q000187:drug effects*; D042301:Sphingomonadaceae / Q000187:drug effects*
chemical_list: D054742:Acyl-Butyrolactones; D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D005456:Fluorescent Dyes; D007659:Ketones; D026901:Membrane Transport Proteins; D054328:Proton Pump Inhibitors; D004996:Ethidium