Novel structural analogues of piperine as inhibitors of the NorA efflux pump of Staphylococcus aureus.
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.
Kumar
Ashwani
A
Biotechnology Division, Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
Khan
Inshad Ali
IA
Koul
Surrinder
S
Koul
Jawahir Lal
JL
Taneja
Subhash Chandra
SC
Ali
Intzar
I
Ali
Furqan
F
Sharma
Sandeep
S
Mirza
Zahid Mehmood
ZM
Kumar
Manoj
M
Sangwan
Pyare Lal
PL
Gupta
Pankaj
P
Thota
Niranjan
N
Qazi
Ghulam Nabi
GN
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
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