title: Novel structural analogues of piperine as inhibitors of the NorA efflux pump of Staphylococcus aureus.
abstract: OBJECTIVE
  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.
authors.affiliation: Biotechnology Division, Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Ashwani
authors.initials: A
authors.lastname: Kumar
authors.forename: Inshad Ali
authors.initials: IA
authors.lastname: Khan
authors.forename: Surrinder
authors.initials: S
authors.lastname: Koul
authors.forename: Jawahir Lal
authors.initials: JL
authors.lastname: Koul
authors.forename: Subhash Chandra
authors.initials: SC
authors.lastname: Taneja
authors.forename: Intzar
authors.initials: I
authors.lastname: Ali
authors.forename: Furqan
authors.initials: F
authors.lastname: Ali
authors.forename: Sandeep
authors.initials: S
authors.lastname: Sharma
authors.forename: Zahid Mehmood
authors.initials: ZM
authors.lastname: Mirza
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.forename: Pyare Lal
authors.initials: PL
authors.lastname: Sangwan
authors.forename: Pankaj
authors.initials: P
authors.lastname: Gupta
authors.forename: Niranjan
authors.initials: N
authors.lastname: Thota
authors.forename: Ghulam Nabi
authors.initials: GN
authors.lastname: Qazi
mesh_terms: D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D052117:Benzodioxoles / Q000737:chemistry* / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D004996:Ethidium / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D015394:Molecular Structure; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D009154:Mutation; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000737:chemistry* / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000470:Alkaloids; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D052117:Benzodioxoles; D002939:Ciprofloxacin; D004996:Ethidium; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010880:Piperidines; D053284:Polyunsaturated Alkamides; C583244:5-(3,4-methylenedioxyphenyl)-4-ethyl-2,4-pentadienoic acid piperidide; C075040:NorA protein, Staphylococcus; C008922:piperine