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

TY - JOUR

T1 - Novel structural analogues of piperine as inhibitors of the NorA efflux pump of Staphylococcus aureus

AU - Kumar, Ashwani

AU - Khan, Inshad Ali

AU - Koul, Surrinder

AU - Koul, Jawahir Lal

AU - Taneja, Subhash Chandra

AU - Ali, Intzar

AU - Ali, Furqan

AU - Sharma, Sandeep

AU - Mirza, Zahid Mehmood

AU - Kumar, Manoj

AU - Sangwan, Pyare Lal

AU - Gupta, Pankaj

AU - Thota, Niranjan

AU - Qazi, Ghulam Nabi

PY - 2008/6

Y1 - 2008/6

N2 - 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.

AB - 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.

KW - Alkaloids

KW - Anti-Bacterial Agents

KW - Bacterial Proteins

KW - Benzodioxoles

KW - Ciprofloxacin

KW - Drug Resistance, Bacterial

KW - Drug Synergism

KW - Ethidium

KW - Microbial Sensitivity Tests

KW - Microbial Viability

KW - Molecular Structure

KW - Multidrug Resistance-Associated Proteins

KW - Mutation

KW - Piperidines

KW - Polyunsaturated Alkamides

KW - Staphylococcus aureus

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1093/jac/dkn088

DO - 10.1093/jac/dkn088

M3 - Journal article

C2 - 18334493

SN - 0305-7453

VL - 61

SP - 1270

EP - 1276

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

IS - 6

ER -