Novel structural analogues of piperine as inhibitors of the NorA efflux pump of Staphylococcus aureus

J Antimicrob Chemother. 2008 Jun;61(6):1270-6. doi: 10.1093/jac/dkn088. Epub 2008 Mar 10.


Objectives: Evaluation of novel synthetic analogues of piperine as inhibitors of multidrug efflux pump NorA of Staphylococcus aureus.

Methods: A library of piperine-derived compounds was evaluated for their potential to inhibit ethidium bromide efflux in NorA-overexpressing S. aureus SA 1199B. The active compounds were then individually combined with ciprofloxacin to study the potentiation of ciprofloxacin's activity.

Results: Based on the efflux inhibition assay, a library of 200 compounds was screened. Three piperine analogues, namely SK-20, SK-56 and SK-29, were found to be the most potent inhibitors of the NorA efflux pump. These inhibitors acted in a synergistic manner with ciprofloxacin, by substantially increasing its activity against both NorA-overexpressing and wild-type S. aureus isolates. These analogues were 2- to 4-fold more potent than piperine at a significantly lower minimal effective concentration. Furthermore, these inhibitors also significantly suppressed the in vitro emergence of ciprofloxacin-resistant S. aureus.

Conclusions: A newly identified class of compounds derived from a natural amide, piperine, is more potent than the parent molecule in potentiating the activity of ciprofloxacin through the inhibition of the NorA efflux pump. These molecules may prove useful in augmenting the antibacterial activities of fluoroquinolones in a clinical setting.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / chemistry*
  • Alkaloids / pharmacology*
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors*
  • Benzodioxoles / chemistry*
  • Benzodioxoles / pharmacology*
  • Ciprofloxacin / pharmacology
  • Drug Resistance, Bacterial
  • Drug Synergism
  • Ethidium / metabolism
  • Microbial Sensitivity Tests
  • Microbial Viability
  • Molecular Structure
  • Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
  • Mutation
  • Piperidines / chemistry*
  • Piperidines / pharmacology*
  • Polyunsaturated Alkamides / chemistry*
  • Polyunsaturated Alkamides / pharmacology*
  • Staphylococcus aureus / drug effects*
  • Staphylococcus aureus / metabolism


  • 5-(3,4-methylenedioxyphenyl)-4-ethyl-2,4-pentadienoic acid piperidide
  • Alkaloids
  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Benzodioxoles
  • Multidrug Resistance-Associated Proteins
  • Piperidines
  • Polyunsaturated Alkamides
  • NorA protein, Staphylococcus
  • Ciprofloxacin
  • Ethidium
  • piperine