title: Efflux inhibition by selective serotonin reuptake inhibitors in Escherichia coli.
abstract: OBJECTIVE
  To evaluate the antimicrobial and synergistic (hypothetically due to the inhibition of efflux pumps) effects of selective serotonin reuptake inhibitors (SSRIs) in Escherichia coli strains overproducing various resistance-nodulation-division (RND) efflux pumps.
  
  
  METHODS
  MICs of various SSRIs and of clinically relevant antibiotics in the presence and absence of sertraline were determined for E. coli strains overproducing the RND efflux pumps AcrAB, AcrEF, MdtEF and MexAB. The effect of sertraline on Nile red efflux was evaluated in a real-time efflux assay. Expression of marA and acrB was monitored using quantitative RT-PCR.
  
  
  RESULTS
  In MIC assays there was limited synergy of sertraline with tetracycline, oxacillin, linezolid and clarithromycin, depending on the individual pump overexpressed and on whether rich or minimal medium was used. Sertraline, as the most potent SSRI with regard to bacterial growth inhibition, led to rapid dose-dependent Nile red efflux inhibition, and was also found to increase the expression of marA and acrB.
  
  
  CONCLUSIONS
  A possible explanation for the discrepancy between the MIC and real-time efflux assays was that sertraline is a weak inducer of marA and acrB, thereby reducing its initial antibacterial and sensitizing effects over time. The results indicate that sertraline may be useful as a model efflux pump inhibitor for in vitro short-term experiments in E. coli, but is unlikely to be clinically useful as a co-drug against Gram-negative bacteria.
authors.affiliation: Center for Infectious Diseases and Travel Medicine, University Hospital, and Department of Medicine, Albert-Ludwigs-University, Freiburg, Germany. juergen@bohnert.name
authors.forename: Jürgen A
authors.initials: JA
authors.lastname: Bohnert
authors.forename: Magdalena
authors.initials: M
authors.lastname: Szymaniak-Vits
authors.forename: Sabine
authors.initials: S
authors.lastname: Schuster
authors.forename: Winfried V
authors.initials: WV
authors.lastname: Kern
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D004357:Drug Synergism; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000096:biosynthesis / Q000235:genetics; D005456:Fluorescent Dyes; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008826:Microbial Sensitivity Tests; D010078:Oxazines; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D020280:Sertraline / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D005456:Fluorescent Dyes; D008565:Membrane Proteins; D010078:Oxazines; D011494:Protein Kinases; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; C080002:MarA protein, E coli; C065271:arcB protein, E coli; C044808:nile red