ABSTRACT
Piperine, a trans-trans-isomer of 1-piperoyl-piperidine, was tested in combination with mupirocin for antimicrobial activity against Staphylococcus aureus strains including meticillin-resistant S. aureus. The combination markedly reduced the MIC of mupirocin and also lowered the mutation frequency. Enhanced accumulation and efflux of ethidium bromide from wild-type and mutant (Mup(r)-1) strains in the presence of piperine indicated that inhibition of efflux could be a possible mechanism of potentiation of mupirocin activity by piperine. The combination of piperine with mupirocin in a dermal infection model of mice showed better in vivo efficacy when compared with the commercially available formulation of 2â% mupirocin.
Subject(s)
Alkaloids/metabolism , Anti-Bacterial Agents/metabolism , Bacterial Proteins/antagonists & inhibitors , Benzodioxoles/metabolism , Enzyme Inhibitors/metabolism , Methicillin-Resistant Staphylococcus aureus/drug effects , Methicillin-Resistant Staphylococcus aureus/enzymology , Piperidines/metabolism , Polyunsaturated Alkamides/metabolism , Alkaloids/therapeutic use , Animals , Anti-Bacterial Agents/therapeutic use , Benzodioxoles/therapeutic use , Disease Models, Animal , Drug Synergism , Enzyme Inhibitors/therapeutic use , Ethidium/metabolism , Female , Membrane Transport Proteins , Mice , Microbial Sensitivity Tests , Mupirocin/metabolism , Piperidines/therapeutic use , Polyunsaturated Alkamides/therapeutic use , Rodent Diseases/drug therapy , Staphylococcal Infections/drug therapy , Treatment OutcomeABSTRACT
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.
Subject(s)
Alkaloids/chemistry , Alkaloids/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Benzodioxoles/chemistry , Benzodioxoles/pharmacology , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Piperidines/chemistry , Piperidines/pharmacology , Polyunsaturated Alkamides/chemistry , Polyunsaturated Alkamides/pharmacology , Staphylococcus aureus/drug effects , Ciprofloxacin/pharmacology , Drug Resistance, Bacterial , Drug Synergism , Ethidium/metabolism , Microbial Sensitivity Tests , Microbial Viability , Molecular Structure , Mutation , Staphylococcus aureus/metabolismABSTRACT
Piperine, a trans-trans isomer of 1-piperoyl-piperidine, in combination with ciprofloxacin markedly reduced the MICs and mutation prevention concentration of ciprofloxacin for Staphylococcus aureus, including methicillin-resistant S. aureus. The enhanced accumulation and decreased efflux of ethidium bromide in the wild-type and mutant (CIPr-1) strains in the presence of piperine suggest its involvement in the inhibition of bacterial efflux pumps.
